Sustained release delivery of active agents to treat glaucoma and ocular hypertension

ABSTRACT

The methods described herein provide treatment of glaucoma, ocular hypertension, and elevated intraocular pressure with latanoprost or other therapeutic agent(s). Implant devices for insertion into a punctum of a patient provide sustained release of latanoprost or other therapeutic agent(s) that is maintained for 7, 14, 21, 30, 45, 60, or 90 days or more, thus avoiding patient noncompliance and reducing or lowering adverse events associated with eye drop administration of latanoprost or other therapeutic agent(s) and other therapeutic agent(s).

CLAIM OF PRIORITY

Benefit of priority is hereby claimed to U.S. Provisional PatentApplication Ser. No. 61/052,068 filed on May 9, 2008 and entitledSustained Release Delivery of Latanoprost to Treat Glaucoma; U.S.Provisional Patent Application Ser. No. 61/052,113 filed on May 9, 2008and entitled Sustained Release Delivery of Latanoprost to TreatGlaucoma; and U.S. Provisional Patent Application Ser. No. 61/108,777filed on Oct. 27, 2008 and entitled Sustained Release Delivery ofLatanoprost to Treat Glaucoma, the specifications of which are hereinincorporated by reference in their entirety.

BACKGROUND OF THE INVENTION

Glaucoma is a collection of disorders characterized by progressivevisual field loss due to optic nerve damage. It is the leading cause ofblindness in the United States, affecting 1-2% of individuals aged 60and over. Although there are many risk factors associated with thedevelopment of glaucoma (age, race, myopia, family history, and injury),elevated intraocular pressure, also known as ocular hypertension, is theonly risk factor successfully manipulated and correlated with thereduction of glaucomatous optic neuropathy. Public health figuresestimate that 2.5 million Americans manifest ocular hypertension.

In order to treat glaucoma and ocular hypertension, drugs are oftenrequired to be administered to the eye. A conventional method of drugdelivery is by topical drop application to the eye's surface. Topicaleye drops, though effective, can be inefficient. For instance, when aneye drop is instilled in an eye, it often overfills the conjunctival sac(i.e., the pocket between the eye and the lids) causing a substantialportion of the drop to be lost due to overflow of the lid margin andspillage onto the cheek. In addition, a large portion of the dropremaining on the ocular surface can be washed away into and through alacrimal canaliculus, thereby diluting the concentration of the drugbefore it can treat the eye. Further, in many cases, topically appliedmedications have a peak ocular effect within about two hours, afterwhich additional applications of the medications should be performed tomaintain the therapeutic benefit. PCT Publication WO 06/014434 (Lazar),which is incorporated herein by reference in its entirety, may berelevant to these or other issues associated with eye drops.

To compound ocular management difficulty, patients often do not usetheir eye drops as prescribed. Noncompliance rates of at least 25%commonly have been reported. This poor compliance can be due to, forexample, an initial stinging or burning sensation caused by the eye dropand experience by a patient. Instilling eye drops in one's own eye canbe difficult, in part because of the normal reflex to protect the eye.Therefore, one or more drops may miss the eye. Older patients may haveadditional problems instilling drops due to arthritis, unsteadiness, anddecreased vision. Pediatric and psychiatric populations posedifficulties as well.

In light of the above, what is needed are improved drug delivery systemsthat overcome at least some of the above shortcomings.

SUMMARY OF THE INVENTION

The present invention provides methods for sustained release delivery ofa therapeutic agent from a punctum of a patient into ocular tissues forthe treatment of a disease, particularly a disease of the eye, using animplant. In one embodiment, the therapeutic agent is latanoprost. In oneaspect, the present invention provides a method of deliveringlatanoprost and/or one or more other therapeutic agent(s) to an eyehaving associated tear fluid, the method comprises placing a topicalformulation comprising latanoprost and/or one or more other therapeuticagent(s) into a punctum of the eye. In one embodiment, the topicalformulation is in a form of a drug core which is optionally disposed ina punctal implant body configured for at least partial insertion into apunctum or canaliculus of the eye. In some embodiments, the drug corecan comprise a matrix and inclusions of a therapeutic agent, in someembodiments latanoprost, within the matrix. A portion of the drug corecan be exposed to the tear in order to release the latanoprost or othertherapeutic agent(s) to the tear. The latanoprost or other therapeuticagent(s) may be dissolved into or dispersed in the matrix and thelatanoprost or other therapeutic agent(s) is released through theexposed portion of the core at therapeutic levels over a sustainedperiod. In another aspect, the present invention provides a method ofdelivering latanoprost or other therapeutic agent(s) to an eye havingassociated tear fluid, the method comprises placing a topicalformulation consisting essentially of latanoprost or other therapeuticagent(s) and a polymer into a punctum of the eye. In one embodiment, thetopical formulation is impregnated within a pre-formed punctal implant,or is made in the form of a punctal implant composed of a mixture oflatanoprost or other therapeutic agent(s) and a polymer.

In some embodiments, the latanoprost or other therapeutic agent(s) canbe released through the exposed portion of the drug core or impregnatedbody at therapeutic levels for about 90 days. The latanoprost or othertherapeutic agent(s) may comprise an oil. The latanoprost or othertherapeutic agent(s) can be encapsulated within the matrix, and thematrix may comprise a non-bioabsorbable polymer.

The present invention provides the use of latanoprost or anothertherapeutic agent or agents for the treatment of elevated intraocularpressure. In some embodiments, the invention provides the use oflatanoprost for treatment of glaucoma. In some embodiments, theinvention provides the use of a therapeutic agent or agents other thanlatanoprost for treatment of glaucoma. In some embodiments, the use oflatanoprost for reducing intraocular pressure is provided. Certainembodiments provide the use of latanoprost or another therapeutic agentor agents for treating diseases of the eye. In some embodiments,combinations of therapeutic agents are provided for use in treatment ofdiseases of the eye. The present invention also provides the use of ananti-glaucoma drug for treatment of glaucoma and/or elevated intraocularpressure. In some embodiments, the present invention provides the use ofa prostaglandin or prostaglandin analogue for treatment of diseases ofthe eye.

The present invention further provides the use of an intraocularpressure-reducing therapeutic agent in the manufacture of a medicamentfor the reduction of intraocular pressure in an eye of a patient in needthereof. In some embodiments, the medicament is a sustained releasetopical formulation. In some embodiments, the intraocularpressure-reducing therapeutic agent is capable of being continuouslyreleased over time to the eye. In certain embodiments, the intraocularpressure of the patient is reduced at least 10% from baseline. Incertain embodiments, the intraocular pressure is reduced at least 15%from baseline, at least 20% from baseline, or at least 25% frombaseline.

In specific embodiments, the intraocular pressure-reducing therapeuticagent is released for a period of time of at least about 30 days, atleast about 60 days, or at least about 90 days. In some embodiments, theintraocular pressure-reducing therapeutic agent is an anti-glaucomadrug, for example an adrenergic agonist, an adrenergic antagonist, abeta blocker, a carbonic anhydrase inhibitor, a parasympathomimetic, aprostaglandin analog, a hypotensive lipid, a neuroprotectant, orcombinations thereof. In one embodiment, the anti-glaucoma drug islatanoprost.

In many embodiments, the formulation is disposed in and eluted from anocular implant, such as a punctal implant. In some embodiments, theformulation is impregnated within the punctal implant such that at leastone surface of the implant is coated with the formulation. In someembodiments, the formulation is contained within a sustained releasecore disposed in the punctal implant.

It is contemplated that the punctal implant can contain an amount ofintraocular pressure-reducing therapeutic agent consisting of about 3.5micrograms, about 14 micrograms, about 21 micrograms or about 44micrograms. In some embodiments, the punctal implant is inserted intoone punctum of each of both eyes of the patient.

The formulation can be administered approximately once every 90 days,and the intraocular pressure-reducing therapeutic agent can becontinuously released to the eye for a period of consisting ofapproximately 180 days, approximately 270 days, approximately 360 days,approximately 450 days, approximately 540 days, approximately 630 days,approximately 720 days, approximately 810 days or approximately 900days.

In certain embodiments, between about 25 ng/day and about 250 ng/day ofthe intraocular pressure-reducing therapeutic agent is released. In oneembodiment, the intraocular pressure is at least about 20 mm Hg beforeadministering the intraocular pressure-reducing therapeutic agent. Insome embodiments, the reduction in intraocular pressure is maintainedfor a continuous period of time consisting of: up to about 7 days, up toabout 14 days, up to about 21 days, up to about 28 days, up to about 56days, up to about 84 days, or up to about 105 days.

In some embodiments, patient noncompliance is significantly reducedcompared to eye drop formulations of intraocular pressure-reducingtherapeutic agents.

In certain embodiments, the intraocular pressure is associated withocular hypertension. In some embodiments, the intraocular pressure isassociated with glaucoma.

Also provided herein is the use of an intraocular pressure-reducingagent in the manufacture of a medicament for the reduction ofintraocular pressure in an eye of a patient in need thereof, wherein themedicament is adapted for use in an implant that is inserted into atleast one punctum of the eye, wherein the implant comprises a sustainedrelease core comprising the intraocular pressure-reducing agent, whereinthe intraocular pressure-reducing therapeutic agent is capable of beingcontinuously released over time to the eye, and wherein the intraocularpressure is reduced at least about 10% from baseline.

In some embodiments, the intraocular pressure is reduced an amountselected from the group consisting of at least 15% from baseline, atleast 20% from baseline and at least 25% from baseline. In certainembodiments, the intraocular pressure-reducing therapeutic agent isreleased for a period of time selected from the group consisting of atleast about 30 days, at least about 60 days, and at least about 90 days.

In some embodiments, the sustained release core is disposed in animplant body. In certain embodiments, the patient is suffering fromglaucoma. In certain embodiments, the implant, the sustained releasecore, or both are at least partially coated by an impermeable coating.In some embodiments, the impermeable coating comprises parylene. In oneembodiment, the intraocular pressure-reducing therapeutic agent islatanoprost.

The present invention also provides a method to reduce intraocularpressure by inserting an implant into at least one punctum of a patient,wherein the implant is at least partially impregnated with latanoprostor other therapeutic agent(s) or includes a sustained release corecontaining at least latanoprost or other therapeutic agent(s), andwherein the implant releases latanoprost or other therapeutic agent(s)continuously for at least about 90 days. In one embodiment, the methodtreats elevated glaucoma-associated intraocular pressure by theinsertion of an implant including latanoprost or other therapeuticagent(s) at least partially into a punctum of a subject to effect thesustained release of latanoprost or other therapeutic agent(s) to thesubject, resulting in a reduction in the intraocular pressure of theassociated eye of at least 6 mm Hg.

In some embodiments, the implant releases latanoprost or othertherapeutic agent(s) during a continuous period of time from at leastabout 7 days, at least about 28 days, at least about 52 days, at leastabout 88 days, or at least about 90 days following insertion of theimplant. In some embodiments, the implant releases between about 25ng/day and about 250 ng/day of latanoprost or other therapeuticagent(s). In other embodiments the implant can release at least 250ng/day of latanoprost or other therapeutic agent(s). In other otherembodiments, the implant can release at least 350 ng/day or more oflatanoprost or other therapeutic agent(s). In certain embodiments, theimplant can release about 0.75 micrograms per day, about 1.0 microgramsper day, or about 1.5 micrograms or more per day of latanoprost or othertherapeutic agent(s). In some embodiments, the topical formulation of animplant comprising latanoprost or other therapeutic agent(s) isadministered to the eyes of a subject less than 10 times, less than 5times, or less than 3 times during the continuous period of time.

In an embodiment, the invention provides a method to reduce intraocularpressure by inserting an implant into at least one punctum of a patienthaving an intraocular pressure (IOP) of about 22 mm Hg. The implant canbe at least partially impregnated with latanoprost or other therapeuticagent(s) or can comprise a sustained release core containing at leastlatanoprost or other therapeutic agent(s), and the release oflatanoprost or other therapeutic agent(s) from the implant results inthe reduction of the IOP from about 22 mm Hg to about 16 mm Hg.

In certain embodiments, the invention provides a method to reduceintraocular pressure by inserting an implant into at least one punctumof a patient having an intraocular pressure (IOP) of about 21 mm Hg,about 20 mm Hg, about 19 mm Hg, about 18 mm Hg, about 17 mm Hg, about 16mm Hg, about 15 mm Hg, about 14 mm Hg, about 13 mm Hg, about 12 mm Hg,about 11 mm Hg, or about 10 mm Hg. In an embodiment, the inventionprovides a method to treat primary open angle glaucoma. In otherembodiments, the invention provides a method to treat angle closureglaucoma. In further embodiments, the invention provides a method totreat normal tension glaucoma. In still further embodiments, theinvention provides a method to treat secondary glaucoma.

In certain embodiments, the reduction in intraocular pressure ismaintained for a continuous period of time of up to about 7 days, up toabout 14 days, up to about 21 days, up to about 28 days, up to about 52days, up to about 88 days, or up to about 105 days. In an embodiment,the reduction in intraocular pressure is maintained for a continuousperiod of time of at least about 90 days. Another embodiment provides acourse of treatment of about 90 days.

In certain embodiments, the variability in intraocular pressure over thecourse of treatment after one week is less than about 1 mm Hg. In otherembodiments, the variability in intraocular pressure over the course oftreatment after one week is less than about 2 mm Hg. In otherembodiments, the variability in intraocular pressure over the course oftreatment after one week is less than about 3 mm Hg. In an embodiment,once the intraocular pressure is reduced by about 6 mm Hg, thevariability in intraocular pressure at any given time point during theremainder of the course of treatment is less than about 1 mm Hg.

The invention described herein also provides a method to reduceintraocular pressure by inserting a sustained release implant into atleast one punctum of a patient wherein the intraocular pressure of theassociated eye is reduced by at least about 25%.

In some embodiments, the invention provides a method to treat a patienthaving ocular hypertension by administering a topical formulationconsisting of latanoprost or other therapeutic agent(s) eluted from adrug core or other implant body that is configured for at least partialinsertion into at least one punctum of a patient, wherein theformulation is capable of reducing intraocular pressure for at least 90days. In an embodiment, the drug core is configured for insertion intoan ocular implant. In still further embodiment, the ocular implant is apunctal implant, for example a punctal plug.

In an embodiment, the methods of the invention result in a reduction inthe intraocular pressure of at least 10% by 1 day after inserting theimplant or at least 20% within 7 days after inserting the implant. Insome embodiments, the reduction in intraocular pressure is maintainedfor at least 75 days. In other embodiments, the reduction in intraocularpressure is maintained for at least 90 days. In other embodiments, thereduction in intraocular pressure is maintained for at least 120 days.In still other embodiments, about 20% reduction, about 25% reduction,about 30% reduction, about 35% reduction, about 40% reduction, about 45%reduction, or about 50% or greater reduction in the intraocular pressureis present at about 90 days or less after insertion of the punctalimplant.

In an embodiment, the intraocular pressure prior to inserting thepunctal implant is at least 20 mm Hg. In some embodiments, theintraocular pressure is about 16 mm Hg about 7 days after inserting theimplant.

The methods of the invention described herein also provide an implant atleast partially impregnated with a therapeutic agent or having asustained release core that includes a non-biodegradable polymer. Insome embodiments, the sustained release core includes silicone.

The implant can be inserted into the upper punctum or the lower punctum,or implants can be inserted into both the upper and lower puncta. Theimplant may be inserted into one punctum of one eye or implants may beinserted into each punctum of both eyes.

The implant may contain at least 3 micrograms, at least 10 micrograms,at least 20 micrograms, at least 30 micrograms, at least 40 micrograms,or between about 3.5 and 135 micrograms of latanoprost or othertherapeutic agent(s). In other embodiments, the implant may contain morethan 40 micrograms of latanoprost or other therapeutic agent(s). Inother embodiments, the implant may contain a therapeutic agent, forexample one or more prostaglandin derivatives, such as travoprost,bimatoprost, etc or other therapeutic agent(s) useful in the treatmentof elevated intraocular pressure, such as beta blockers, carbonicanhydrase inhibitors, alpha adrenergic antagonists, and the like. Insome embodiments, the amount of the therapeutic agent or agents releasedfrom the implant is sufficient to treat an ocular condition for asustained period of time, for example about 7 days or longer, about 30days or longer, about 45 days or longer, about 60 days or longer, about75 days or longer, about 90 days, or longer. In some embodiments, theimplant contains about 3.5 micrograms, about 14 micrograms, about 21micrograms, about 42 micrograms or about 44 micrograms of latanoprost orother therapeutic agent(s). In other embodiments, the implant containsabout 50, about 60, about 70 or about 80 micrograms of latanoprost orother therapeutic agent(s). In other embodiments, the implant containssufficient quantities of therapeutic agent for sustained release attherapeutic levels over the desired treatment period.

The invention further provides a method to treat elevated intraocularpressure by inserting an implant into at least one punctum of a patient,wherein the implant is impregnated with or has a sustained release corecontaining about 14 micrograms of latanoprost or other therapeuticagent(s), wherein the implant remains inserted for at least 90 days, andwherein the intraocular pressure is reduced substantially as shown inFIG. 1.

In some embodiments, a topical formulation consisting essentially oflatanoprost or other therapeutic agent(s) and a pharmaceuticallyacceptable vehicle is provided, wherein the formulation is eluted from asolid drug core or other implant body configured for at least partialinsertion into at least one punctum of a patient, wherein theformulation is capable of reducing intraocular pressure for at least 90days.

The invention further provides a reduction in patient noncompliancecompared to eye drop formulations of latanoprost and other therapeuticagent(s). A single insertion procedure provides continuousadministration of latanoprost or other therapeutic agent(s) for asustained period of time, avoiding patient noncompliance that isassociated with eye drop administration.

The invention further provides a method of reducing intraocular pressureand in some embodiments, lowering the occurrence of adverse effects dueto topical administration of therapeutic agents for treating eyediseases, for example prostaglandins including but not limited tolatanoprost, travoprost, and bimatoprost, and as a further example,timolol, comprising delivering said therapeutic agents to the eye froman implant including but not limited to the implants as disclosedherein. In an embodiment such implant may be partially or completelyimpregnated with said therapeutic agents. For instance, the implant bodycan comprise a matrix of a polymeric component and one or moretherapeutic agents. The one or more therapeutic agents can bedistributed substantially thought the matrix and released over time. Inanother embodiment, such implant may comprise a sustained release drugcore containing said therapeutic agents.

BRIEF DESCRIPTION OF THE FIGURES

In the drawings, like numerals can be used to describe similarcomponents throughout the several views. The drawings illustrategenerally, by way of example, but not by way of limitation, variousembodiments discussed in the present document.

FIG. 1 illustrates mean intraocular pressure in subjects treated with 14μg Latanoprost Punctal Plug Delivery System.

FIG. 2A illustrates an example of an isometric view of a punctal implantconfigured to be retained at least partially within a lacrimal punctumor canalicular anatomy.

FIG. 2B illustrates an example of a cross-sectional view of a punctalimplant taken along a line parallel to a longitudinal axis of theimplant, such as along line 2B-2B of FIG. 2A.

FIG. 2C illustrates an example of a cross-sectional view of anotherpunctal implant taken along a line parallel to a longitudinal axis ofthe implant.

FIG. 3A illustrates an example of an isometric view of a punctal implantconfigured to be retained at least partially within a lacrimal punctumor canalicular anatomy.

FIG. 3B illustrates an example of a cross-sectional view of a punctalimplant taken along a line parallel to a longitudinal axis of theimplant, such as along line 3B-3B of FIG. 3A, and a dilation of animplant-receiving anatomical tissue structure.

FIG. 4A illustrates an example of an isometric view of a punctal implantconfigured to be retained at least partially within a lacrimal punctumor canalicular anatomy.

FIG. 4B illustrates an example of a cross-sectional view of a punctalimplant taken along a line parallel to a longitudinal axis of theimplant, such as along line 4B-4B of FIG. 4A.

FIG. 5 illustrates an example of a cross-sectional view of a punctalimplant configured to be retained at least partially within a lacrimalpunctum or canalicular anatomy.

FIG. 6 illustrates intraocular pressure values over three months offollow-up.

FIG. 7 illustrates intraocular pressure values with greater than threemonths of follow-up.

FIG. 8 illustrates mean intraocular pressure change from baseline(+/−SD) over three months time.

FIG. 9 illustrates mean IOP changes from baseline in the CORE study.

FIG. 10 illustrates mean IOP changes from baseline in the CORE study.

FIG. 11 illustrates decreases in IOP at Week 12 in the CORE study.

FIG. 12 illustrates percent reduction in IOP in the CORE study comparedto a published latanoprost and timolol-eye drop study (Source: USLatanoprost Study Group. Rate of Response to Latanoprost or Timolol inPatients with Ocular Hypertension or Glaucoma. J Glaucoma 2003;12:466-469). Note, percentages for latanoprost and timolol are estimatesfrom graphs in source.

FIG. 13 illustrates percent reduction in IOP in the CORE study comparedto published latanoprost, timolol and bimatoprost eye drop studies(References: Rate of Response to Latanoprost or Timolol in Patients withOcular Hypertension or Glaucoma. J Glaucoma 2003; 12:466-469; ASix-month Randomized Clinical Trial Comparing the IntraocularPressure-lowering efficacy of Bimatoprost and Latanoprost in PatientsWith Ocular Hypertension or Glaucoma. Am J Ophthalmol 2003; 135:55-63).Percentages for latanoprost and timolol are estimates from graphs.

FIG. 14 illustrates absolute reduction in IOP in the CORE study comparedto a published latanoprost and timolol eye drop study. Source: USLatanoprost Study Group. Rate of Response to Latanoprost or Timolol inPatients with Ocular Hypertension or Glaucoma. J Glaucoma 2003;12:466-469. Note: Percentages for latanoprost and timolol are estimatesfrom graphs in source.

FIG. 15 illustrates the percentage of patients reaching target IOP inthe CORE study compared to a published latanoprost and timolol eye dropstudy. Source: US Latanoprost Study Group. Rate of Response toLatanoprost or Timolol in Patients with Ocular Hypertension or Glaucoma.J Glaucoma 2003; 12:466-469. Note: Percentages for latanoprost andtimolol are estimates from graphs in source.

FIG. 16 illustrates ocular adverse events (AEs) in the CORE study.

FIG. 17 illustrates ocular adverse events in the CORE study compared tolatanoprost eye drop studies. * Xalatan Ophthalmic Solution 0.005% (50mg/mL) (Pharmacia) Jun. 5, 1996 Approval: Medical Officers Review, pp.93, 98-100. Provided by FOI Services. ** A Six-month Randomized ClinicalTrial Comparing the Intraocular Pressure-lowering efficacy ofBimatoprost and Latanoprost in Patients with Ocular Hypertension orGlaucoma. Am J Ophthalmol 2003; 135:55-63. *Other adverse eventsincluded eyelash growth. *** Of 198 patients (p. 98 of XalatanOphthalmic Solution 0.005% (50 mg/mL) (Pharmacia) Jun. 5, 1996 Approval:Medical Officers Review).

FIG. 18 illustrates ocular adverse events in the CORE study compared toeye drop studies of latanoprost, travoprost, timolol, and bimatoprost.(1) Travoprost Compared With Latanoprost and Timolol in Patients WithOpen-angle Glaucoma or Ocular Hypertension. Am J Ophthalmol 2001;132:472-484. *Other AEs included ocular pain, cataract, dry eye,blepharitis, blurred vision. (2) A Six-month Randomized Clinical TrialComparing the Intraocular Pressure-lowering efficacy of Bimatoprost andLatanoprost in Patients With Ocular Hypertension or Glaucoma. Am JOphthalmol 2003; 135:55-63. *Other AEs included eyelash growth.

-   -   (3) One-Year, Randomized Study Comparing Bimatoprost and Timolol        in Glaucoma and Ocular Hypertension. Arch Ophthalmol V 120        October 2002 1286-1293. *Other AEs included eyelash growth, eye        dryness, eye pain. Also included bimatoprost BID group (higher        AE incidence).

DETAILED DESCRIPTION OF THE INVENTION Definitions

As used herein, the terms “a” or “an” are used, as is common in patentdocuments, to include one or more than one, independent of any otherinstances or usages of “at least one” or “one or more.”

As used herein, the term “or” is used to refer to a nonexclusive or,such that “A or B” includes “A but not B,” “B but not A,” and “A and B,”unless otherwise indicated.

As used herein, the term “about” is used to refer to an amount that isapproximately, nearly, almost, or in the vicinity of being equal to astated amount.

As used herein, the term “adverse event” refers to any undesirableclinical event experienced by a patient undergoing a therapeutictreatment including a drug and/or a medical device, whether in aclinical trial or a clinical practice. Adverse events include a changein the patient's condition or laboratory results, which has or couldhave a deleterious effect on the patient's health or well-being. Forexample, adverse events include but are not limited to: devicemalfunction identified prior to placement, device malposition, devicemalfunction after placement, persistent inflammation, endophthalmitis,corneal complications (corneal edema, opacification, or graftdecompensation), chronic pain, iris pigmentation changes, conjunctivalhyperemia, eyelash growth (increased length, thickness, pigmentation,and number of lashes), eyelid skin darkening, intraocular inflammation(iritis/uveitis), macular edema including cystoid macular edema, blurredvision, burning and stinging, foreign body sensation, itching, punctateepithelial keratopathy, dry eye, excessive tearing, eye pain, lidcrusting, lid discomfort/pain, lid edema, lid erythema, photophobia, VAdecrease, conjunctivitis, diplopia, discharge from the eye, retinalartery embolus, retinal detachment, vitreous hemorrhage from diabeticretinopathy, upper respiratory tract infection/cold/flu, chestpain/angina pectoris, muscle/joint/back pain, and rash/allergic skinreaction, eye pruritus, increase in lacrimation, ocular hyperemia andpunctate keratitis.

As used herein, the phrase “consisting essentially of” limits acomposition to the specified materials or steps and those additional,undefined components that do not materially affect the basic and novelcharacteristic(s) of the composition.

As used herein, the term “continuous” or “continuously” means unbrokenor uninterrupted. For example, continuously administered active agentsare administered over a period of time without interruption.

As used herein, the term “eye” refers to any and all anatomical tissuesand structures associated with an eye. The eye is a spherical structurewith a wall having three layers: the outer sclera, the middle choroidlayer and the inner retina. The sclera includes a tough fibrous coatingthat protects the inner layers. It is mostly white except for thetransparent area at the front, the cornea, which allows light to enterthe eye. The choroid layer, situated inside the sclera, contains manyblood vessels and is modified at the front of the eye as the pigmentediris. The biconvex lens is situated just behind the pupil. The chamberbehind the lens is filled with vitreous humour, a gelatinous substance.The anterior and posterior chambers are situated between the cornea andiris, respectively and filled with aqueous humour. At the back of theeye is the light-detecting retina. The cornea is an opticallytransparent tissue that conveys images to the back of the eye. Itincludes avascular tissue to which nutrients and oxygen are supplied viabathing with lacrimal fluid and aqueous humour as well as from bloodvessels that line the junction between the cornea and sclera. The corneaincludes one pathway fro the permeation of drugs into the eye. Otheranatomical tissue structures associated with the eye include thelacrimal drainage system, which includes a secretory system, adistributive system and an excretory system. The secretory systemcomprises secretors that are stimulated by blinking and temperaturechange due to tear evaporation and reflex secretors that have anefferent parasympathetic nerve supply and secrete tears in response tophysical or emotional stimulation. The distributive system includes theeyelids and the tear meniscus around the lid edges of an open eye, whichspread tears over the ocular surface by blinking, thus reducing dryareas from developing.

As used herein, the term “implant” refers to a structure that can beconfigured to contain or be impregnated with a drug, for example via adrug core or a drug matrix, such as those as disclosed in this patentdocument and in WO 07/115,261, which is herein incorporated by referencein its entirety, and which is capable of releasing a quantity of activeagent, such as latanoprost or other therapeutic agent(s), into tearfluid for a sustained release period of time when the structure isimplanted at a target location along the path of the tear fluid in thepatient. The terms “implant,” “plug,” “punctal plug,” and “punctalimplant” are meant herein to refer to similar structures. Likewise, theterms “implant body” and “plug body” are meant herein to refer tosimilar structures. The implants described herein may be inserted intothe punctum of a subject, or through the punctum into the canaliculus.The implant may be also the drug core or drug matrix itself, which isconfigured for insertion into the punctum without being housed in acarrier such as a punctal implant occluder, for example having apolymeric component and a latanoprost or other therapeutic agent(s)component with no additional structure surrounding the polymericcomponent and latanoprost or other therapeutic agent(s) component.

As used herein, “loss of efficacy” (LoE) is defined as an IOP increaseto baseline (post-washout) IOP in either or both eyes while wearing anL-PPDS continuously from Day 0. Subjects were followed for at least 4weeks before the subject could complete the study due to LoE and LoE wasconfirmed at 2 sequential visits.

As used herein, a “pharmaceutically acceptable vehicle” is anyphysiological vehicle known to those of ordinary skill in the art usefulin formulating pharmaceutical compositions. Suitable vehicles includepolymeric matrices, sterile distilled or purified water, isotonicsolutions such as isotonic sodium chloride or boric acid solutions,phosphate buffered saline (PBS), propylene glycol and butylene glycol.Other suitable vehicular constituents include phenylmercuric nitrate,sodium sulfate, sodium sulfite, sodium phosphate and monosodiumphosphate. Additional examples of other suitable vehicle ingredientsinclude alcohols, fats and oils, polymers, surfactants, fatty acids,silicone oils, humectants, moisturizers, viscosity modifiers,emulsifiers and stabilizers. The compositions may also contain auxiliarysubstances, i.e. antimicrobial agents such as chlorobutanol, parabans ororganic mercurial compounds; pH adjusting agents such as sodiumhydroxide, hydrochloric acid or sulfuric acid; and viscosity increasingagents such as methylcellulose. The final composition should be sterile,essentially free of foreign particles, and have a pH that allows foroptimum drug stability.

As used herein, the term “punctum” refers to the orifice at the terminusof the lacrimal canaliculus, seen on the margins of the eyelids at thelateral extremity of the lacus lacrimalis. Puncta (plural of punctum)function to reabsorb tears produced by the lacrimal glands. Theexcretory part of the lacrimal drainage system includes, in flow orderof drainage, the lacrimal puncta, the lacrimal canaliculi, the lacrimalsac and the lacrimal duct. From the lacrimal duct, tears and otherflowable materials drain into a passage of the nasal system. Thelacrimal canaliculi include an upper (superior) lacrimal canaliculus anda lower (inferior) lacrimal canaliculus, which respectively terminate inan upper and lower lacrimal punctum. The upper and lower punctum areslightly elevated at the medial end of a lid margin at the junction ofthe ciliary and lacrimal portions near a conjunctival sac. The upper andlower punctum are generally round or slightly ovoid openings surroundedby a connective ring of tissue. Each of the puncta leads into a verticalportion of their respective canaliculus before turning more horizontalat a canaliculus curvature to join one another at the entrance of thelacrimal sac. The canaliculi are generally tubular in shape and lined bystratified squamous epithelium surrounded by elastic tissue, whichpermits them to be dilated.

The terms “subject” and “patient” refer to animals such as mammals,including, but not limited to, primates (e.g., humans), cows, sheep,goats, horses, dogs, cats, rabbits, rats, mice and the like. In manyembodiments, the subject or patient is a human.

A “therapeutic agent” can comprise a drug and may be any of thefollowing or their equivalents, derivatives or analogs, includinganti-glaucoma medications (e.g. adrenergic agonists, adrenergicantagonists (beta blockers), carbonic anhydrase inhibitors (CAIs,systemic and topical), parasympathomimetics (e.g. cholinergic drug),prostaglandins and hypotensive lipids, and combinations thereof),antimicrobial agents (e.g., antibiotic, antiviral, antiparacytic,antifungal, etc.), a corticosteroid or other anti-inflammatory (e.g., anNSAID), a decongestant (e.g., vasoconstrictor), an agent that preventsof modifies an allergic response (e.g., an antihistamine, cytokineinhibitor, leucotriene inhibitor, IgE inhibitor, immunomodulator), amast cell stabilizer, cycloplegic or the like. Examples of conditionsthat may be treated with the therapeutic agent(s) include but are notlimited to glaucoma, pre and post surgical treatments, ocularhypertension, dry eye and allergies. In some embodiments, thetherapeutic agent may be a lubricant or a surfactant, for example alubricant to treat dry eye.

Exemplary therapeutic agents include, but are not limited to thrombininhibitors; antithrombogenic agents; thrombolytic agents; fibrinolyticagents; vasospasm inhibitors; vasodilators; antihypertensive agents;antimicrobial agents, such as antibiotics (such as tetracycline,chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin,cephalexin, oxytetracycline, chloramphenicol, rifampicin, ciprofloxacin,tobramycin, gentamycin, erythromycin, penicillin, sulfonamides,sulfadiazine, sulfacetamide, sulfamethizole, sulfisoxazole,nitrofurazone, sodium propionate), antifungals (such as amphotericin Band miconazole), and antivirals (such as idoxuridine trifluorothymidine,acyclovir, gancyclovir, interferon); inhibitors of surface glycoproteinreceptors; antiplatelet agents; antimitotics; microtubule inhibitors;anti-secretory agents; active inhibitors; remodeling inhibitors;antisense nucleotides; anti-metabolites; antiproliferatives (includingantiangiogenesis agents); anticancer chemotherapeutic agents;anti-inflammatories (such as hydrocortisone, hydrocortisone acetate,dexamethasone 21-phosphate, fluocinolone, medrysone, methylprednisolone,prednisolone 21-phosphate, prednisolone acetate, fluoromethalone,betamethasone, triamcinolone, triamcinolone acetonide); non steroidalanti-inflammatories (NSAIDs, such as salicylate, indomethacin,ibuprofen, diclofenac, flurbiprofen, piroxicam indomethacin, ibuprofen,naxopren, piroxicam and nabumetone). Such anti inflammatory steroidscontemplated for use in the methodology of the present invention,include triamcinolone acetonide (generic name) and corticosteroids thatinclude, for example, triamcinolone, dexamethasone, fluocinolone,cortisone, prednisolone, flumetholone, and derivatives thereof);antiallergenics (such as sodium chromoglycate, antazoline,methapyriline, chlorpheniramine, cetrizine, pyrilamine,prophenpyridamine); anti proliferative agents (such as 1,3-cis retinoicacid, 5-fluorouracil, taxol, rapamycin, mitomycin C and cisplatin);decongestants (such as phenylephrine, naphazoline, tetrahydrazoline);miotics and anti-cholinesterase (such as pilocarpine, salicylate,carbachol, acetylcholine chloride, physostigmine, eserine, diisopropylfluorophosphate, phospholine iodine, demecarium bromide);antineoplastics (such as carmustine, cisplatin, fluorouracil3;immunological drugs (such as vaccines and immune stimulants); hormonalagents (such as estrogens, -estradiol, progestational, progesterone,insulin, calcitonin, parathyroid hormone, peptide and vasopressinhypothalamus releasing factor); immunosuppressive agents, growth hormoneantagonists, growth factors (such as epidermal growth factor, fibroblastgrowth factor, platelet derived growth factor, transforming growthfactor beta, somatotrapin, fibronectin); inhibitors of angiogenesis(such as angiostatin, anecortave acetate, thrombospondin, anti-VEGFantibody); dopamine agonists; radiotherapeutic agents; peptides;proteins; enzymes; extracellular matrix; components; ACE inhibitors;free radical scavengers; chelators; antioxidants; anti polymerases;photodynamic therapy agents; gene therapy agents; and other therapeuticagent(s) such as prostaglandins, antiprostaglandins, prostaglandinprecursors, including antiglaucoma drugs including beta-blockers such asTimolol, betaxolol, levobunolol, atenolol, and prostaglandin analoguessuch as Bimatoprost, travoprost, Latanoprost, etc; carbonic anhydraseinhibitors such as acetazolamide, dorzolamide, brinzolamide,methazolamide, dichlorphenamide, diamox; and neuroprotectants such aslubezole, nimodipine and related compounds; and parasympathomimetricssuch as pilocarpine, carbachol, physostigmine and the like.

The term “topical” refers to any surface of a body tissue or organ. Atopical formulation is one that is applied to a body surface, such as aneye, to treat that surface or organ. Topical formulations as used hereinalso include formulations that can release therapeutic agents into thetears to result in topical administration to the eye.

As used herein, the term “treating” or “treatment” of a diseaseincludes: (1) preventing the disease, i.e., causing the clinicalsymptoms of the disease not to develop in a subject that may be exposedto or predisposed to the disease but who does not yet experience ordisplay symptoms of the disease; (2) inhibiting the disease, i.e.,arresting or reducing the development of the disease or its clinicalsymptoms; or (3) relieving the disease, i.e., causing regression of thedisease or its clinical symptoms.

The implants described herein are contemplated to be useful fortreatment of various diseases including, but not limited to, diseases ormalconditions of the eye. These diseases or malconditions includediabetic retinopathy, uveitis, intraocular inflammation, keratitis, dryeye, macular edema including cystoid macular edema, infection, maculardegeneration, blurred vision, herpetic conjunctivitis, blepharitis,retinal or choroidal neovascularizaton, and other proliferative eyediseases. Also contemplated herein is the treatment of additionaldiseases including, but not limited to, rheumatic disease, dizziness,infectious diseases including upper respiratory tract infections(cold/flu), chest pain/angina pectoris, heart disease, muscle/joint/backpain, autoimmune disease, inflammatory conditions, cancer or otherproliferative diseases, infections, vascular disease, diabetes anddiseases of the central nervous system including migraine headache. Bothlocal and systemic delivery of therapeutic agents from the plugsdescribed herein may be employed.

The invention provides the use of latanoprost or another active agent oragents for treatment of diabetic retinopathy, uveitis, intraocularinflammation, keratitis, dry eye, macular edema including cystoidmacular edema, infection, macular degeneration, blurred vision, herpeticconjunctivitis, blepharitis, retinal or choroidal neovascularizaton, andother proliferative eye diseases. Also provided herein is the use oflatanoprost or other active agent(s) for treatment of rheumatic disease,dizziness, infectious diseases including upper respiratory tractinfections (cold/flu), chest pain/angina pectoris, heart disease,muscle/joint/back pain, autoimmune disease, inflammatory conditions,cancer or other proliferative disease, infections, vascular disease,diabetes and diseases of the central nervous system including migraineheadache. In some embodiments, the invention provides the use of ananti-glaucoma drug for treatment of the above diseases. In certainembodiments, the use of a prostaglandin or prostaglandin analogue fortreatment of the above diseases is provided.

Elevated Intraocular Pressure:

Ocular hypertension (OH) and primary open angle glaucoma (POAG) arecaused by a build-up of aqueous humor in the anterior chamber primarilydue to the eye's inability to properly drain aqueous fluid. The ciliarybody, situated at the root of the iris, continuously produces aqueoushumor. It flows into the anterior chamber and then drains via the anglebetween the cornea and iris through the trabecular meshwork and into achannel in the sclera. In the normal eye, the amount of aqueous humorbeing produced is equal to the amount that is draining out. However, inan eye in which this mechanism is compromised, intraocular pressure(IOP) rises. Elevated IOP represents a major risk factor forglaucomatous field loss. Results from several studies indicate thatearly intervention targeted at lowering intraocular pressure retards theprogression of optic nerve damage and loss of visual fields that lead todecreased vision and blindness.

Latanoprost:

A preferred therapeutic agent for use in the methods described herein islatanoprost. Latanoprost is a prostaglandin F_(2α) analogue. Itschemical name is isopropyl-(Z)-7[(1R,2R,3R,5S)3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl]-5-heptenoate.Its molecular formula is C₂₆H₄₀O₅ and its chemical structure is:

Latanoprost is a colorless to slightly yellow oil that is very solublein acetonitrile and freely soluble in acetone, ethanol, ethyl acetate,isopropanol, methanol and octanol. It is practically insoluble in water.

Latanoprost is believed to reduce intraocular pressure (IOP) byincreasing the outflow of aqueous humor. Studies in animals and mansuggest that the main mechanism of action is increased uveoscleraloutflow of aqueous fluid from the eyes. Latanoprost is absorbed throughthe cornea where the isopropyl ester prodrug is hydrolyzed to the acidform to become biologically active. Studies in man indicate that thepeak concentration in the aqueous humor is reached about two hours aftertopical administration.

Xalatan® latanoprost ophthalmic solution is a commercially availableproduct indicated for the reduction of elevated IOP in patients withopen-angle glaucoma or ocular hypertension. The amount of latanoprost inthe commercially available product Xalatan® is approximately 1.5micrograms/drop. As described above, eye drops, though effective, can beinefficient and require multiple applications to maintain thetherapeutic benefit. Low patient compliance compounds these effects.

Patient Noncompliance:

Numerous studies have been published showing high noncompliance bypatients using eye drops for treatment of various ocular disorders. Onestudy showed only 64% of patients used the eye drops as directed(Winfield et al., 1990). Another study showed that 41% of patients usingeye drops for glaucoma missed six or more doses over a 30-day period(Norell and Granstrom 1980).

The invention described herein provides methods to treat glaucoma thatavoid the problem of noncompliance associated with eye dropadministration. In some embodiments, the methods of the invention reducepatient noncompliance significantly compared to eye drop administration,by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%,at least 60%, at least 70%, at least 80%, or at least 90%. In someembodiments, overall patient noncompliance with the methods describedherein is about 5%, about 10%, about 15%, about 20%, or about 25%.

Patient noncompliance may occur if an implant of the invention isintentionally removed by a patient or if the patient does not seekreinsertion of the implant after such implant has been unintentionallylost from the punctum of the patient. Patient compliance is consideredto be met if the implant is intentionally removed and the patient seeksreinsertion within less than about 48 hours. Patient compliance is alsoconsidered to be met if the implant is intentionally removed and thepatient seeks reinsertion within less than about 24 hours of removal orloss of the implant.

Adverse Events in Clinical Trials and Clinical Practice:

Based on Xalatan® product information, the most frequently reportedocular adverse events associated with latanoprost in clinical trialswere blurred vision, burning and stinging, conjunctival hyperemia,foreign body sensation, itching, increased pigmentation of the iris, andpunctate keratopathy. These events occurred in 5% to 15% of subjects.Less than 1% of subjects required discontinuation of therapy because ofintolerance to conjunctival hyperemia. Dry eye, excessive tearing, eyepain, lid crusting, lid discomfort/pain, lid edema, lid erythema, andphotophobia were reported in 1% to 4% of subjects. Conjunctivitis,diplopia, and discharge from the eye were reported in <1% of subjects.Retinal artery embolus, retinal detachment, and vitreous hemorrhage fromdiabetic retinopathy were rarely reported.

The most common systemic adverse events in clinical trials were upperrespiratory tract infection/cold/flu, which occurred at a rate ofapproximately 4%. Chest pain/angina pectoris, muscle/joint/back pain,and rash/allergic skin reaction each occurred at a rate of 1% to 2%.

In clinical practice, the following adverse events associated withlatanoprost have been noted: asthma and exacerbation of asthma; cornealedema and erosions; dyspnea; eyelash and vellus hair changes (increasedlength, thickness, pigmentation, and number); eyelid skin darkening;herpes keratitis; intraocular inflammation (iritis/uveitis); keratitis;macular edema, including cystoid macular edema; misdirected eyelashessometimes resulting in eye irritation; dizziness, headache, and toxicepidermal necrolysis.

Methods of Treatment:

The invention described herein provides methods to treat glaucoma,elevated intraocular pressure, and glaucoma-associated elevatedintraocular pressure with a therapeutic agent. In many embodiments, amethod of treating an eye with latanoprost is provided. In someembodiments, the therapeutic agent is released to the eye over asustained period of time. In an embodiment, the sustained period of timeis approximately 90 days. In some embodiments, the method comprisesinserting through a punctum an implant having a body and a drug core sothat the drug core is retained near the punctum. In some embodiments,the method comprises inserting through a punctum an implant having abody impregnated with a therapeutic agent. In some embodiments, anexposed surface of the drug core or impregnated body located near theproximal end of the implant contacts the tear or tear film fluid and thelatanoprost or other therapeutic agent(s) migrates from the exposedsurface to the eye over a sustained period of time while the drug coreand body is at least partially retained within the punctum. In manyembodiments, a method of treating an eye with latanoprost or othertherapeutic agent(s) is provided, the method comprising insertingthrough a punctum into a canalicular lumen an implant having an optionalretention structure so that the implant body is anchored to a wall ofthe lumen by the retention structure. The implant releases effectiveamounts of latanoprost or other therapeutic agent(s) from a drug core orother agent supply into a tear or tear film fluid of the eye. In someembodiments, the drug core may be removed from the retention structurewhile the retention structure remains anchored within the lumen. Areplacement drug core can then be attached to the retention structurewhile the retention structure remains anchored. At least one exposedsurface of the replacement drug core releases latanoprost or othertherapeutic agent(s) at therapeutic levels over a sustained period.

A replacement implant, or in other embodiments, a replacement drug corewhich can in some embodiments be attached to or include its ownretention structure, can be attached to the retention structureapproximately every 90 days to result in continuous release of the drugto the eye for a period of time of approximately 180 days, approximately270 days, approximately 360 days, approximately 450 days, approximately540 days, approximately 630 days, approximately 720 days, approximately810 days or approximately 900 days. In some embodiments, a replacementimplant can be inserted into the punctum approximately every 90 days toachieve release of the drug to the eye for extended periods of time,including up to about 180 days, about 270 days, about 360 days, about450 days, about 540 days, about 630 days, about 720 days, about 810 daysor about 900 days.

In other embodiments, a method for treating an eye with latanoprost orother therapeutic agent(s) is provided, the method comprising insertinga drug core or other implant body at least partially into at least onepunctum of the eye. The drug core may or may not be associated with aseparate implant body structure. The drug core or agent-impregnatedimplant body provides sustained release delivery of latanoprost or othertherapeutic agent(s) at therapeutic levels. In some embodiments, thesustained release delivery of latanoprost or other therapeutic agent(s)continues for up to 90 days.

In many embodiments, a method for treating an eye with latanoprost orother therapeutic agent(s) is provided, the method comprising insertinga distal end of an implant into at least one punctum of the eye. In someembodiment, a retention structure of the implant can be expanded so asto inhibit expulsion of the implant. The expansion of the retentionstructure can help to occlude a flow of tear fluid through the punctum.In some embodiments, the implant is configured such that, whenimplanted, an at least 45 degree angled intersection exists between afirst axis, defined by a proximal end of the implant, and a second axis,defined by the distal end of the implant, to inhibit expulsion of theimplant. Latanoprost or other therapeutic agent(s) is delivered from aproximal end of the implant to the tear fluid adjacent the eye. Deliveryof the latanoprost or other therapeutic agent(s) is inhibited distallyof the proximal end.

The methods of the invention provide sustained release of latanoprost orother therapeutic agent(s). In some embodiments, the active agent isreleased from the implant for at least one week, at least two weeks, atleast three weeks, at least four weeks, at least five weeks, at leastsix weeks, at least seven weeks, at least eight weeks, at least nineweeks, at least ten weeks, at least eleven weeks, at least twelve weeks,at least thirteen weeks, at least fourteen weeks, at least fifteenweeks, or at least sixteen weeks. In some embodiments, the active agentis latanoprost. In an embodiment, the latanoprost or other therapeuticagent(s) is released for at least twelve weeks. In another embodiment,the methods of treatment according to the present invention as describedabove further comprises an adjunctive therapy with alatanoprost-delivering eye drop solution, for example, Xalatan®.

The amount of latanoprost or other therapeutic agent(s) associated withthe implant may vary depending on the desired therapeutic benefit andthe time during which the device is intended to deliver the therapy.Since the devices of the present invention present a variety of shapes,sizes and delivery mechanisms, the amount of drug associated with thedevice will depend on the particular disease or condition to be treated,and the dosage and duration that is desired to achieve the therapeuticeffect. Generally, the amount of latanoprost or other therapeuticagent(s) is at least the amount of drug that, upon release from thedevice, is effective to achieve the desired physiological orpharmacological local or systemic effects.

Certain embodiments of the implants of the present invention can beconfigured to provide delivery of latanoprost or other therapeuticagent(s) at daily rates that are similar or equivalent to thetherapeutically effective drop form of treatment. Other embodiments ofthe implants of the present invention can be configured to providedelivery of latanoprost or other therapeutic agent(s) at daily ratesthat exceed the therapeutically effective drop form of treatment.

Embodiments of the implants of the present invention can also beconfigured to provide delivery of latanoprost or other therapeuticagent(s) at a daily rate that is substantially below the therapeuticallyeffective drop form of treatment so as to provide a large therapeuticrange with a wide safety margin. For example, many embodiments treat theeye with therapeutic levels for extended periods that are no more than 5or 10 percent of the daily drop dosage. In specific embodiments, thequantity can be less than 5% of the recommended drop-administeredquantity. Consequently, during an initial bolus or washout period ofabout one to three days, the implant can elute latanoprost or othertherapeutic agent(s) at a rate that is substantially higher than thesustained release levels and well below the daily drop form dosage. Forexample, with an average sustained release level of 100 ng per day, andan initial release rate of 1000 to 1500 ng per day, the amount of druginitially released is less than the 2500 ng of drug that may be presentin a drop of drug delivered to the eye. This use of sustained releaselevels substantially below the amount of drug in one or more dropsadministered daily allows the device to release a therapeuticallybeneficial amount of drug to achieve the desired therapeutic benefitwith a wide safety margin, while avoiding an inadequate or excessiveamount of drug at the intended site or region.

For comparison purposes, standard treatment with drops such as Xalatan®drops delivers about 1.5 micrograms of latanoprost, assuming a 35microliter drop volume. In contrast, in one embodiment, the implant ofthe instant invention can deliver an amount of drug that will besignificantly less than conventional drop administration describedabove. In other embodiments, the sustained release of more than 100 ngper day, for example, up to 1.5 micrograms of latanoprost per day, canbe administered. Although the sustained release amount of latanoprostreleased each day can vary, a sustained release of approximately 100 ngper day using the implant of the invention corresponds to about 6% ofthe latanoprost applied with a single drop of a 0.005% solution.

Methods of inserting and removing the implant are known to those ofskill in the art. For instance, tools for insertion andremoval/extraction of implants are described in U.S. Patent ApplicationNo. 60/970,840 (filed Sep. 7, 2007 and entitled Insertion and ExtractionTools for Punctal Implants), the disclosure of which is incorporatedherein in its entirety. Generally, for placement, the size of a punctalimplant to be used may be determined by using suitable magnification or,if provided, using a sizing tool that accompanies the punctal implant.The patient's punctum may be dilated if necessary to fit the punctalimplant. A drop of lubricant may be applied if necessary to facilitateplacement of the implant into the punctum. Using an appropriateplacement instrument, the implant may be inserted into the superior orinferior punctum of the eye. After placement, the cap of the implant maybe visible. This process may be repeated for the patient's other eye.For removal of the implant, small surgical forceps may be used tosecurely grasp the implant at the tube section below the cap. Using agentle tugging motion the implant may be gently retrieved.

Implant:

In some embodiments, latanoprost or other therapeutic agent(s) isadministered for a sustained period of time by a drug matrix core whichmay or may not be associated with a separate implant body structure. Incertain embodiments, an implant for use in the methods described hereinis provided. The implant can be configured, when implanted at a targetlocation along the path of tear fluid in the patient, to release aquantity of latanoprost or other therapeutic agent(s) into the tearfluid each day for a sustained release period of days, weeks, or months.The implant can be one of any number of different designs that releaseslatanoprost or other therapeutic agent(s) for a sustained period oftime. The disclosures of the following patent documents, which describeexample implant structure or processing embodiments for use in themethods of the current invention and methods of making those implants,are incorporated herein by reference in their entirety: U.S. ApplicationSer. No. 60/871,864 (filed Dec. 26, 2006 and entitled NasolacrimalDrainage System Implants for Drug Therapy); U.S. application Ser. No.11/695,537 (filed Apr. 2, 2007 and entitled Drug Delivery Methods,Structures, and Compositions for Nasolacrimal System); U.S. ApplicationSer. No. 60/787,775 (filed Mar. 31, 2006 and entitled NasolacrimalDrainage System Implants for Drug Therapy); U.S. application Ser. No.11/695,545 (filed Apr. 2, 2007 and entitled Nasolacrimal drainage systemimplants for drug therapy); U.S. application Ser. No. 11/571,147 (filedDec. 21, 2006 and entitled Treatment Medium Delivery Device and Methodsfor Delivery of Such Treatment Mediums to the Eye Using Such a DeliveryDevice); U.S. Application Ser. No. 60/970,696 (filed Sep. 7, 2007 andentitled Expandable Nasolacrimal Drainage System Implants); U.S.Application Ser. No. 60/974,367 (filed Sep. 21, 2007 and entitledExpandable Nasolacrimal Drainage System Implants); U.S. Application Ser.No. 60/970,699 (filed Sep. 7, 2007 and entitled Manufacture of DrugCores for Sustained Release of Therapeutic Agents); U.S. ApplicationSer. No. 60/970,709 (filed Sep. 7, 2007 and entitled NasolacrimalDrainage System Implants for Drug Delivery); U.S. Application Ser. No.60/970,720 (filed Sep. 7, 2007 and entitled Manufacture of ExpandableNasolacrimal Drainage System Implants); U.S. Application Ser. No.60/970,755 (filed Sep. 7, 2007 and entitled Prostaglandin Analogues forImplant Devices and Methods); U.S. Application Ser. No. 60/970,820(filed Sep. 7, 2007 and entitled Multiple Drug Delivery Systems andCombinations of Drugs with Punctal Implants); U.S. Application Ser. No.61/049,347 (filed Apr. 30, 2008 and entitled Lacrimal Implants andRelated Methods); U.S. Application Ser. No. 61/049,360 (filed Apr. 30,2008 and entitled Lacrimal Implants and Related Methods); U.S.Application Ser. No. 61/052,595 (filed May 12, 2008 and entitledLacrimal Implants and Related Methods); U.S. Application Ser. No.61/075,309 (filed Jun. 24, 2008 and entitled Lacrimal Implants andRelated Methods); U.S. Application Ser. No. 61/154,693 (filed Feb. 23,2009 and entitled Lacrimal Implants and Related Methods); U.S.Application Ser. No. 61/209,036 (filed Mar. 2, 2009 and entitledLacrimal Implants and Related Methods); U.S. Application Ser. No.61/209,630 (filed Mar. 9, 2009 and entitled Lacrimal Implants andRelated Methods); U.S. Application Ser. No. 61/036,816 (filed Mar. 14,2008 and entitled Lacrimal Implants and Related Methods); U.S.Application Ser. No. 61/049,337 (filed Apr. 30, 2008 and entitledLacrimal Implants and Related Methods); U.S. application Ser. No.12/432,553 (filed Apr. 29, 2009 and entitled Composite Lacrimal Insertand Related Methods); U.S. Application Ser. No. 61/049,317 (filed Apr.30, 2008 and entitled Drug-Releasing Polyurethane Lacrimal Insert); U.S.application Ser. No. 12/378,710 (filed Feb. 17, 2009 and entitledLacrimal Implants and Related Methods); U.S. application Ser. No.12/283,002 (filed Sep. 5, 2008 and entitled Surface Treated ImplantableArticles and Related Methods); U.S. application Ser. No. 12/231,989(filed Sep. 5, 2008 and entitled Lacrimal Implants and Related Methods);U.S. application Ser. No. 12/231,986 (filed Sep. 5, 2008 and entitledDrug Cores for Sustained Release of Therapeutic Agents); U.S.application Ser. No. 12/231,987 (filed Sep. 5, 2008 and entitledLacrimal Implant Detection); U.S. application Ser. No. 10/825,047 (filedApr. 15, 2004 and entitled Drug Delivery via Punctal Plug);International Published Application WO 2006/014434; and InternationalApplication Serial No. PCT/US2007/065789 (filed Mar. 31, 2006, publishedas WO 2007/115259 and entitled Nasolacrimal Drainage System Implants forDrug Therapy).

Generally, the implant comprises a body. In some embodiments, theimplant body has a distal end portion and a proximal end portion. Thedistal end portion of the body is at least partially insertable into thepunctum to the canalicular lumen of the patient. The implant body may beat least impregnated with latanoprost or other therapeutic agent(s) orotherwise comprise latanoprost or other therapeutic agent(s), such aswithin a matrix drug core that is inserted into the implant body.Exposure of the matrix drug core or impregnated body to the tear fluidcauses an effective release of latanoprost or other active agent intothe tear fluid over a sustained period. The implant may include a sheathdisposed over at least a portion of the drug core to inhibit release oflatanoprost or other therapeutic agent(s) from certain portions thereof.The implant body may have an outer surface configured to engage luminalwall tissues so as to inhibit expulsion when disposed therein. In manyembodiments, an integral feedback or other projection is connectedaround the sheath near the proximal end of the drug core. In anembodiment, the feedback or other projection includes one or more wingssized to remain outside the punctum so as to retain the proximal end ofthe drug core near the punctum. In other embodiments, the feedback orother projection includes a full or partial (e.g., trimmed) head portionconnected around the sheath near the proximal end of the drug core. Thehead portion can be sized to remain outside the punctum so as to retainthe proximal end of the drug core near the punctum.

In some embodiments, the implant comprises a drug core alone, lacking anadditional structure surrounding the core. For example, in someembodiments, the implant may comprise a body formed of a drug elutingmatrix, such as silicone, and a prostaglandin or other therapeuticagent, in some embodiments, latanoprost, wherein the therapeutic agentis impregnated in part or all of implant body, such as those describedin U.S. application Ser. No. 10/825,047 (filed Apr. 15, 2004 andentitled Drug Delivery via Punctal Plug). In some embodiments, the drugcore comprises a latanoprost or other therapeutic agent(s) matrixcomprising a pharmaceutically acceptable vehicle, for example, anon-bioabsorbable polymer, for example silicone in a non-homogenousmixture with the latanoprost or other therapeutic agent(s). Thenon-homogeneous mixture in the drug core may comprise a silicone matrixsaturated with the latanoprost or other therapeutic agent(s) or withinclusions of latanoprost or other therapeutic agent(s). The inclusionsin the drug core are a concentrated form of latanoprost or othertherapeutic agent(s), and the silicone matrix encapsulates theinclusions in the drug core. In specific embodiments, the latanoprost orother therapeutic agent(s) inclusions encapsulated within the siliconematrix comprise an inhomogeneous mixture of the inclusions encapsulatedwithin the silicone matrix. The drug core inclusions can compriselatanoprost oil.

It is also within the scope of this invention to modify or adapt theimplant device to deliver a high release rate, a low release rate, abolus release, a burst release, or combinations thereof. A bolus of thedrug may be released by the formation of an erodable polymer cap that isimmediately dissolved in the tear or tear film. As the polymer cap comesin contact with the tear or tear film, the solubility properties of thepolymer enable the cap to erode and the latanoprost or other therapeuticagent(s) is released all at once. A burst release of latanoprost orother therapeutic agent(s) can be performed using a polymer that alsoerodes in the tear or tear film based on the polymer solubility. In thisexample, the drug and polymer may be stratified along the length of thedevice so that as the outer polymer layer dissolves, the drug isimmediately released. A high or low release rate of the drug could beaccomplished by changing the solubility of the erodable polymer layer sothat the drug layer released quickly or slowly. Other methods to releasethe latanoprost or other therapeutic agent(s) could be achieved throughporous membranes, soluble gels (such as those in typical ophthalmicsolutions), microparticle encapsulations of the drug, or nanoparticleencapsulation.

Sheath Body:

The sheath body can comprise appropriate shapes and materials to controlthe migration of latanoprost or other therapeutic agent(s) from the drugcore. In some embodiments, the sheath body houses the drug core and canfit snugly against the core. The sheath body is made from a materialthat is substantially impermeable to the latanoprost or othertherapeutic agent(s) so that the rate of migration of latanoprost orother therapeutic agent(s) may be largely controlled by the exposedsurface area of the drug core that is not covered by the sheath body. Inmany embodiments, migration of the latanoprost or other therapeuticagent(s) through the sheath body can be about one tenth of the migrationof latanoprost or other therapeutic agent(s) through the exposed surfaceof the drug core, or less, often being one hundredth or less. In otherwords, the migration of the latanoprost or other therapeutic agent(s)through the sheath body is at least about an order of magnitude lessthat the migration of latanoprost or other therapeutic agent(s) throughthe exposed surface of the drug core. Suitable sheath body materialsinclude polyimide, polyethylene terephthalate (hereinafter “PET”). Insome embodiments, the sheath body has a thickness, as defined from thesheath surface adjacent the core to the opposing sheath surface awayfrom the core, from about 0.00025″ to about 0.0015″. In someembodiments, the total diameter of the sheath that extends across thecore ranges from about 0.2 mm to about 1.2 mm. The core may be formed bydip coating the core in the sheath material. Alternatively or incombination, the sheath body can comprise a tube and the core introducedinto the sheath, for example as a liquid or solid that can be slid,injected or extruded into the sheath body tube. The sheath body can alsobe dip coated around the core, for example dip coated around apre-formed core.

The sheath body can be provided with additional features to facilitateclinical use of the implant. For example, the sheath may receive a drugcore that is exchangeable while the implant body, retention structureand sheath body remain implanted in the patient. The sheath body isoften rigidly attached to the retention structure as described above,and the core is exchangeable while the retention structure retains thesheath body. In specific embodiments, the sheath body can be providedwith external protrusions that apply force to the sheath body whensqueezed and eject the core from the sheath body. Another drug core canthen be positioned in the sheath body. In many embodiments, the sheathbody or retention structure may have a distinguishing feature, forexample a distinguishing color, to show placement such that theplacement of the sheath body or retention structure in the canaliculusor other body tissue structure can be readily detected by the patient.The retention element or sheath body may comprise at least one mark toindicate the depth of placement in the canaliculus such that theretention element or sheath body can be positioned to a desired depth inthe canaliculus based on the at least one mark.

Retention Structure:

In many embodiments, a retention structure is employed to retain theimplant in the punctum or canaliculus. The retention structure isattached to or integral with the implant body. The retention structurecomprises an appropriate material that is sized and shaped so that theimplant can be easily positioned in the desired tissue location, forexample, the punctum or canaliculus. In some embodiments, the drug coremay be attached to the retention structure via, at least in part, thesheath. In some embodiments, the retention structure comprises ahydrogel configured to expand when the retention structure is placed inthe punctum. The retention structure can comprise an attachment memberhaving an axially oriented surface. In some embodiments, expansion ofthe hydrogel can urge against the axially oriented surface to retain thehydrogel while the hydrogel is hydrated. In some embodiments, theattachment member can comprise at least one of a protrusion, a flange, arim, or an opening through a portion of the retention structure. In someembodiments, the retention structure includes an implant body portionsize and shape to substantially match an anatomy of the punctum andcanaliculus.

The retention structure may have a size suitable to fit at leastpartially within the canalicular lumen. The retention structure can beexpandable between a small profile configuration suitable for insertionand a large profile configuration to anchor the retention structure inthe lumen, and the retention structure can be attached near the distalend of the drug core. In specific embodiments, the retention structurecan slide along the drug core near the proximal end when the retentionstructure expands from the small profile configuration to the largeprofile configuration. A length of the retention structure along thedrug core can be shorter in the large profile configuration than thesmall profile configuration.

In some embodiments, the retention structure is resiliently expandable.The small profile may have a cross section of no more than about 0.2 mm,and the large profile may have a cross section of no more than about 2.0mm. The retention structure may comprise a tubular body having armsseparated by slots. The retention structure can be disposed at leastpartially over the drug core.

In some embodiments, the retention structure is mechanically deployableand typically expands to a desired cross sectional shape, for examplewith the retention structure comprising a super elastic shape memoryalloy such as Nitinol™. Other materials in addition to Nitinol™ can beused, for example resilient metals or polymers, plastically deformablemetals or polymers, shape memory polymers, and the like, to provide thedesired expansion. In some embodiments polymers and coated fibersavailable from Biogeneral, Inc. of San Diego, Calif. may be used. Manymetals such as stainless steels and non-shape memory alloys can be usedand provide the desired expansion. This expansion capability permits theimplant to fit in hollow tissue structures of varying sizes, for examplecanaliculae ranging from 0.3 mm to 1.2 mm (i.e. one size fits all).Although a single retention structure can be made to fit canaliculaefrom 0.3 to 1.2 mm across, a plurality of alternatively selectableretention structures can be used to fit this range if desired, forexample a first retention structure for canaliculae from 0.3 to about0.9 mm and a second retention structure for canaliculae from about 0.9to 1.2 mm. The retention structure has a length appropriate to theanatomical structure to which the retention structure attaches, forexample a length of about 3 mm for a retention structure positioned nearthe punctum of the canaliculus. For different anatomical structures, thelength can be appropriate to provide adequate retention force, e.g. 1 mmto 15 mm lengths as appropriate.

Although the implant body may be attached to one end of the retentionstructure as described above, in many embodiments the other end of theretention structure is not attached to the implant body so that theretention structure can slide over the implant body including the sheathbody and drug core while the retention structure expands. This slidingcapability on one end is desirable as the retention structure may shrinkin length as the retention structure expands in width to assume thedesired cross sectional width. However, it should be noted that manyembodiments may employ a sheath body that does not slide in relative tothe core.

In many embodiments, the retention structure can be retrieved fromtissue. A projection, for example a hook, a loop, or a ring, can extendfrom a portion of the implant body to facilitate removal of theretention structure.

In some embodiments the sheath and retention structure can comprise twoparts.

Occlusive Element:

An occlusive element can be mounted to and expandable with the retentionstructure to inhibit tear flow. An occlusive element may inhibit tearflow through the lumen, and the occlusive element may cover at least aportion of the retention structure to protect the lumen from theretention structure. The occlusive element comprises an appropriatematerial that is sized and shaped so that the implant can at leastpartially inhibit, even block, the flow of fluid through the hollowtissue structure, for example lacrimal fluid through the canaliculus.The occlusive material may be a thin walled membrane of a biocompatiblematerial, for example silicone, that can expand and contract with theretention structure. The occlusive element is formed as a separate thintube of material that is slid over the end of the retention structureand anchored to one end of the retention structure as described above.Alternatively, the occlusive element can be formed by dip coating theretention structure in a biocompatible polymer, for example siliconepolymer. The thickness of the occlusive element can be in a range fromabout 0.01 mm to about 0.15 mm, and often from about 0.05 mm to 0.1 mm.

Drug Core:

In some embodiments, the drug core may be inserted into an implant body,or may serve as the implant itself, without any additional structuralcomponents, or may be configured to adopt the shape of a punctal plug orthe like. The drug core comprises latanoprost or other therapeuticagent(s) and materials to provide sustained release of the latanoprostor other therapeutic agent(s). In some embodiments, the drug corecomprises a sustained release formulation, which formulation consists ofor consists essentially of latanoprost or other therapeutic agent(s) andsilicone as a carrier. The latanoprost or other therapeutic agent(s)migrates from the drug core to the target tissue, for example ciliarymuscles of the eye. The drug core may optionally comprise latanoprost orother therapeutic agent(s) in a matrix, wherein the latanoprost or othertherapeutic agent(s) is dispersed or dissolved within the matrix. Thelatanoprost or other therapeutic agent(s) may be only slightly solublein the matrix so that a small amount is dissolved in the matrix andavailable for release from the surface of the drug core. As thelatanoprost or other therapeutic agent(s) diffuses from the exposedsurface of the core to the tear or tear film, the rate of migration fromthe core to the tear or tear film can be related to the concentration oflatanoprost or other therapeutic agent(s) dissolved in the matrix. Inaddition or in combination, the rate of migration of latanoprost orother therapeutic agent(s) from the core to the tear or tear film can berelated to properties of the matrix in which the latanoprost or othertherapeutic agent(s) is dissolved.

In an embodiment, the topical formulation or the drug core does notcontain a preservative. Preservatives include, for example, benzalkoniumchloride and EDTA. In an embodiment, the implants of the invention maybe less allergenic and may reduce chemical sensitivity compared toformulations containing these preservatives.

In specific embodiments, the rate of migration from the drug core to thetear or tear film can be based on a silicone formulation. In someembodiments, the concentration of latanoprost or other therapeuticagent(s) dissolved in the drug core may be controlled to provide thedesired rate of release of the latanoprost or other therapeuticagent(s). The latanoprost or other therapeutic agent(s) included in thecore can include liquid (such as oil), solid, solid gel, solidcrystalline, solid amorphous, solid particulate, or dissolved forms oflatanoprost or other therapeutic agent(s). In a some embodiments, thedrug core may comprise liquid or solid inclusions, for example liquidLatanoprost or other therapeutic agent(s) droplets dispersed in thesilicone matrix.

Table 1 shows drug insert silicones that may be used and associated cureproperties, according to embodiments of the present invention. The drugcore insert matrix material can include a base polymer comprisingdimethyl siloxane, such as MED-4011, MED 6385 and MED 6380, each ofwhich is commercially available from NuSil. The base polymer can becured with a cure system such as a platinum-vinyl hydride cure system ora tin-alkoxy cure system, both commercially available from NuSil. Inmany embodiments, the cure system may comprise a known cure systemcommercially available for a known material, for example a knownplatinum vinyl hydride cure system with known MED-4011. In a specificembodiment shown in Table 1, 90 parts of MED-4011 can be combined with10 parts of the crosslinker, such that the crosslinker comprises 10% ofthe mixture. A mixture with MED-6385 may comprise 2.5% of thecrosslinker, and mixtures of MED-6380 may comprise 2.5% or 5% of thecrosslinker.

TABLE 1 Drug Insert Silicone Selections Crosslinker Material BasePolymer Cure System Percent MED-4011 Dimethyl siloxane Platinum vinyl 10% Silica filler hydride system material 10% MED-6385 Dimethylsiloxane Tin-Alkoxy 2.5% 2.5% Diatomaceous earth filler materialMED-6380 Dimethyl siloxane Tin-Alkoxy 2.5 to 5% without filler material

It has been determined according to the present invention that the curesystem and type of silicone material can affect the curing properties ofthe solid drug core insert, and may potentially affect the yield oftherapeutic agent from the drug core matrix material. In specificembodiments, curing of MED-4011 with the platinum vinyl hydride systemcan be inhibited with high concentrations of drug/prodrug, for exampleover 20% drug, such that a solid drug core may not be formed. Inspecific embodiments, curing of MED-6385 or MED 6380 with the tin alkoxysystem can be slightly inhibited with high concentrations, e.g. 20%, ofdrug/prodrug. This slight inhibition of curing can be compensated byincreasing the time or temperature of the curing process. For example,embodiments of the present invention can make drug cores comprising 40%drug and 60% MED-6385 with the tin alkoxy system using appropriate curetimes and temperatures. Similar results can be obtained with theMED-6380 system the tin-alkoxy system and an appropriate curing time ortemperature. Even with the excellent results for the tin alkoxy curesystem, it has been determined according to the present invention thatthere may be an upper limit, for example 50% drug/prodrug or more, atwhich the tin-alkoxy cure system may not produce a solid drug core. Inmany embodiments, the latanoprost or other therapeutic agent(s) in thesolid drug core may be at least about 5%, for example a range from about5% to 50%, and can be from about 20% to about 40% by weight of the drugcore.

The drug core or other agent supply (e.g., implant impregnated body) cancomprise one or more biocompatible materials capable of providingsustained release of latanoprost or other therapeutic agent(s). Althoughthe drug core is described above with respect to an embodimentcomprising a matrix with a substantially non-biodegradable siliconematrix with inclusions of latanoprost or other therapeutic agent(s)located therein that dissolve, the drug core can include structures thatprovide sustained release of latanoprost or other therapeutic agent(s),for example a biodegradable matrix, a porous drug core, liquid drugcores and solid drug cores.

A matrix that contains latanoprost or other therapeutic agent(s) can beformed from either biodegradable or non-biodegradable polymers. Anon-biodegradable drug core can include silicone, acrylates,polyethylenes, polyurethane, polyurethane, hydrogel, polyester (e.g.,DACRON™ from E. I. Du Pont de Nemours and Company, Wilmington, Del.),polypropylene, polytetrafluoroethylene (PTFE), expanded PTFE (ePTFE),polyether ether ketone (PEEK), nylon, extruded collagen, polymer foam,silicone rubber, polyethylene terephthalate, ultra high molecular weightpolyethylene, polycarbonate urethane, polyurethane, polyimides,stainless steel, nickel-titanium alloy (e.g., Nitinol), titanium,stainless steel, cobalt-chrome alloy (e.g., ELGILOY™ from ElginSpecialty Metals, Elgin, Ill.; CONICHROME™ from Carpenter Metals Corp.,Wyomissing, Pa.).

A biodegradable drug core can comprise one or more biodegradablepolymers, such as protein, hydrogel, polyglycolic acid (PGA), polylacticacid (PLA), poly(L-lactic acid) (PLLA), poly(L-glycolic acid) (PLGA),polyglycolide, poly-L-lactide, poly-D-lactide, poly(amino acids),polydioxanone, polycaprolactone, polygluconate, polylacticacid-polyethylene oxide copolymers, modified cellulose, collagen,polyorthoesters, polyhydroxybutyrate, polyanhydride, polyphosphoester,poly(alpha-hydroxy acid) and combinations thereof. In some embodimentsthe drug core can comprise at least one hydrogel polymer.

Specific Implant Embodiments:

Various embodiments of the implant that may be employed in the methodsdescribed herein are as follows (see also the Example section below). Insome embodiments, the drug insert includes a thin-walled polyimide tubesheath body that is filled with latanoprost or other therapeuticagent(s) dispersed in Nusil 6385, a cured medical grade solid silicone.The cured silicone serves as the solid, non-erodible matrix from whichlatanoprost or other therapeutic agent(s) slowly elutes. The drug insertis sealed at the distal end with a cured film of solid Loctite 4305medical grade adhesive (cyanoacrylate). The polyimide tube sheath bodyis inert and, together with the adhesive, provides structural supportand a barrier to both lateral drug diffusion and drug diffusion throughthe distal end of the drug insert. The drug insert is seated in the boreof the punctal implant and is held in place via an interference fit. Insome embodiments, a body of the implant is at least partiallyimpregnated with a therapeutic agent, such as latanoprost or othertherapeutic agent(s).

FIG. 2A illustrates an example embodiment of a punctal implant 200 thatis insertable into a lacrimal punctum. The insertion of the punctalimplant 200 into the lacrimal punctum allows for one or more ofinhibition or blockage of tear flow therethrough (e.g., to treat dryeyes) or the sustained delivery of a therapeutic agent to an eye (e.g.,to treat one or more of infection, inflammation, glaucoma or otherocular diseases). In this embodiment, the punctal implant 200 comprisesan implant body 202 extending from a proximal end portion 204 to adistal end portion 206 and having a retention structure 208.

In various embodiments, the implant body 202 can comprise an elasticmaterial, such as silicone, polyurethane or other urethane-basedmaterial, or an acrylic of a non-biodegradable, partially biodegradableor biodegradable nature (i.e., erodeable within the body) allowing atleast one portion of the retention structure to deform outward. In someembodiments, the biodegradable elastic materials include cross-linkedpolymers, such as poly(vinyl alcohol). In some embodiments, differentportions of the implant body 202 are made of different materials. Forinstance, the implant body proximal end portion 204 can comprise asilicone/polyurethane co-polymer and the implant body distal end portion206 can comprise a polyurethane hydrogel or other solid hydrogel. Incertain embodiments, the implant body proximal end portion 204 cancomprise silicone and the implant body distal end portion 206 cancomprise a hydrophilic silicone mixture. Other co-polymers that can beused to form the implant body 302 include silicone/urethane,silicone/poly(ethylene glycol) (PEG), and silicone/2hydroxyethylmethacrylate (HEMA).

In certain embodiments, the implant body 202 can include acylindrical-like structure having a first chamber 210 at or near theproximal end and a second chamber 212 at or near the distal end. Alatanoprost or other therapeutic agent(s) drug core 214 can be disposedin the first chamber 210, while a hydrogel or other expandable retentionelement 216 of a biodegradable or non-biodegradable nature can bedisposed in the second chamber 216. In some embodiments, thebiodegradable retention elements include salt and cellulose basedmixtures. In some embodiments, the non-biodegradable retention elementsinclude hydrogels or other synthetic polymers. An implant body septum218 can be positioned between the first chamber 210 and the secondchamber 216 and can be used to inhibit or prevent communication of amaterial between the drug core 214 and the hydrogel retention element216.

In various ways, the expandable, hydrogel retention element 216 can besubstantially encapsulated, such as within a portion of the retentionstructure 208. In various embodiments, the retention structure 208 caninclude a fluid permeable retainer allowing fluid to be received intoand absorbed or otherwise retained by the hydrogel retention element216, such as upon its insertion into the punctum. The hydrogel retentionelement 216 can be configured to expand, such as to a size or shape thaturges one or more outer surface portions of the retention structure 208to contact a wall of the lacrimal canaliculus, thereby retaining orhelping retain a least a portion of the punctal implant within thepunctum. In some embodiments, the fluid permeable retainer can include afluid permeable aperture 220, such as disposed in a lateral wall of theretention structure 208. In some embodiments, the fluid permeableretainer can include a fluid permeable or hydrophilic cap member 222 orother membrane. In some embodiments, the fluid permeable retainer caninclude a fluid permeable or hydrophilic implant body portion 224. Theseexamples of fluid permeable retainers 220, 222, and 224 can also inhibitthe hydrogel retention element 216 from appreciably protruding out ofthe retention structure 208 during and upon expansion.

The implant body 202 can include a feedback or other projection 226,such as extending laterally at least partially from or around (e.g., aremoval loop) a proximal end portion 204 of the implant body 202. Insome embodiments, the projection 226 can include a removal loop. In someembodiments, the projection 226 can be configured to seat against ornear (e.g., via a ramped portion 260) the punctum opening, such as forinhibiting or preventing the punctal implant 200 from passing completelywithin the canaliculus, or for providing tactile or visual feedbackinformation to an implanting user regarding the same. In someembodiments, a proximal end of the projection 226 can include a convexsuch as for helping provide comfort to a patient when implanted. In someembodiments, the projection 226 can include a convex radius of about 0.8millimeters. In some embodiments, the projection 226 is between about0.7 millimeters to about 0.9 millimeters in diameter. In someembodiments, the projection 226 can include a non-concave shape of about0.5 millimeters to about 1.5 millimeters in diameter, and 0.1millimeters to about 0.75 millimeters in thickness. In some embodiments,the projection 226 has a wing-like shape, in which a column-likeprojection extends from opposite sides of the implant body proximal end204. In some examples, the projection 226 includes a partially trimmedhead portion extending 360 degrees around the proximal end 204 from anouter implant body surface. In some examples, such the projection 226includes a full head portion extending 360 degrees around the proximalend 204 from an outer implant body surface. In an example, theprojection 226 includes a cross-sectional shape similar to a flat disk(i.e., relatively flat top and bottom surfaces). A drug or other agentelution port 228 can extend though the projection 226, such as toprovide sustained release of a drug core 214 agent onto an eye.

FIG. 2B illustrates a cross-sectional view of an example embodiment of apunctal implant 200 taken along a line parallel to a longitudinal axisof the implant, such as along line 2B-2B of FIG. 2A. As shown in FIG.2B, the punctal implant can include an implant body 202 having aretention structure 208 substantially encapsulating a hydrogel retentionelement 216 at or near an implant body distal end portion 206, and alatanoprost or other therapeutic agent(s) drug core 214 disposed withinthe implant body, for example at or near a proximal end portion 204. Inthis embodiment, the drug core 214 is disposed in a first implant bodychamber 210 and the hydrogel retention element 216 is disposed in asecond implant body chamber 212. As discussed above, the hydrogelretention element 216 can be configured to expand to a size or shapethat retains or helps retain at least a portion of the implant 200within the lacrimal punctum. In some embodiments, a hydrogel retentionelement 250 can also be coated or otherwise provided on an outer surfaceportion of the implant body 202 providing another (e.g., secondary)mechanism for retaining or helping to retain at least a portion of theimplant 200 at least partially within the lacrimal punctum.

The retention structure 208, which can be used to substantiallyencapsulate the hydrogel retention element 216, can be of varying sizesrelative to an implant body 202 size. In some embodiments, the retentionstructure 208 at least about one fifth the length of the implant body202. In some embodiments, the retention structure 208 is at least aboutone fourth the length of the implant body 202. In some embodiments, theretention structure 208 is at least about one third the length of theimplant body 202. In some embodiments, the retention structure 208 is atleast about one half the length of the implant body 202. In someembodiments, the retention structure 208 is at least about threequarters the length of the implant body 202. In some embodiments, theretention structure 208 is about the full length of the implant body202.

As shown in the example embodiment of FIG. 2B, the hydrogel retentionelement 216 can have a non-expanded, “dry” state, which aids insertionthrough the punctum and into the lacrimal canaliculus. Once placed inthe canaliculus, the hydrogel retention element 216 can absorb orotherwise retain canalicular or other fluid, such as via a fluidpermeable retainer 220, 222, 224 (FIG. 2A) to form an expandedstructure. In some embodiments, the hydrogel retention element 216 caninclude a material that is non-biodegradable. In some embodiments, thehydrogel retention element 216 can include a material that isbiodegradable. Other options for the hydrogel retention element 216 canalso be used. For instance, the hydrogel retention element 216 can bemolded with the retention structure 208 in a single piece, or can beformed separately as one piece and subsequently coupled to the retentionstructure 208.

In some examples, the drug core 214 disposed at or near the proximal endportion 204 of the implant body 202 can include a plurality oflatanoprost or other therapeutic agent(s) inclusions 252, which can bedistributed in a matrix 254. In some embodiments, the inclusions 252comprise a concentrated form of the latanoprost or other therapeuticagent(s) (e.g., a crystalline agent form). In some embodiments, thematrix 254 can comprise a silicone matrix or the like, and thedistribution of inclusions 252 within the matrix can be non-homogeneous.In some embodiments, the agent inclusions 252 include droplets of anoil, such as latanoprost oil. In still other embodiments, the agentinclusions 252 comprise solid particles. The inclusions can be of manysizes and shapes. For instance, the inclusions can be microparticleshaving dimensions on the order of about 1 micrometers to about 100micrometers.

In the embodiment shown, the drug core 214 has a sheath body 256disposed over at least a portion thereof such as to define at least oneexposed surface 258 of the drug core. The exposed surface 258 can belocated at or near the proximal end portion 204 of the implant body suchas to contact a tear or a tear film fluid and release the latanoprost orother therapeutic agent(s) at one or more therapeutic levels over asustained time period when the punctal implant 200 is inserted into thepunctum.

FIG. 2C illustrates a cross-sectional view of an example embodiment of apunctal implant 200 taken along a line parallel to a longitudinal axisof the implant. As shown in FIG. 2C, the punctal implant includes animplant body 202 without a feedback or other projection 226 (FIG. 2A).In this way, the implant 200 can be completely inserted inside thelacrimal punctum. In some embodiments, the first chamber 210 can includedimensions of about 0.013 inches×about 0.045 inches. In someembodiments, the second chamber 212 can include dimensions of about0.013 inches by about 0.020 inches.

FIG. 3A illustrates another embodiment of a punctal implant 300 that canbe insertable into a lacrimal punctum. The insertion of the punctalimplant 300 into the lacrimal punctum can allow for one or more of:inhibition or blockage of tear flow therethrough (e.g., to treat dryeyes) or the sustained delivery of a therapeutic agent to an eye (e.g.,to treat an infection, inflammation, glaucoma or other ocular disease ordisorder), a nasal passage (e.g., to treat a sinus or allergy disorder)or an inner ear system (e.g., to treat dizziness or a migraine).

In this embodiment, the punctal implant 300 comprises an implant body302 including first 304 and second 306 portions. The implant body 302extends from a proximal end 308 of the first portion 304 to a distal end310 of the second portion 306. In various embodiments, the proximal end308 can define a longitudinal proximal axis 312 and the distal end 310can define a longitudinal distal axis 314. The implant body 300 can beconfigured such that, when implanted, an at least 45 degree angledintersection 316 exists between the proximal axis 312 and the distalaxis 314 for biasing at least a portion of the implant body 302 againstat least a portion of a lacrimal canaliculus located at or more distalto a canaliculus curvature. In some embodiments, the implant body 302can be configured such that the angled intersection 316 is between about45 degrees and about 135 degrees. In this embodiment, the implant body302 is configured such that the angled intersection 316 is approximatelyabout 90 degrees. In various embodiments, a distal end 326 of the firstportion 304 can be integral with the second portion 306 at or near aproximal end 328 of the second portion 306.

In certain embodiments, the implant body 302 can include angularlydisposed cylindrical-like structures comprising one or both of a firstcavity 318 disposed near the proximal end 308 or a second cavity 320disposed near the distal end 310. In this embodiment, the first cavity318 extends inward from the proximal end 308 of the first portion 304,and the second cavity 320 extends inward from the distal end 310 of thesecond portion 306. A first drug-releasing drug supply 322 can bedisposed in the first cavity 318 to provide a sustained drug release toan eye, while a second drug-releasing or other agent-releasing drugsupply 324 can be disposed in the second cavity 320 to provide asustained drug or other agent release to a nasal passage or inner earsystem, for example. An implant body septum 330 can be positionedbetween the first cavity 318 and the second cavity 320, and can be usedto inhibit or prevent communication of a material between the first drugsupply 322 and the second drug supply 324.

In some embodiments, the drug or other agent release can occur, at leastin part, via an exposed surface of the drug supply 322, 324. In someembodiments, by controlling geometry of the exposed surface, apredetermined drug or agent release rate can be achieved. For instance,the exposed surface can be constructed with a specific geometry or othertechnique appropriate to control the release rate of the drug or otheragent onto an eye, such as on an acute basis, or on a chronic basisbetween outpatient doctor visits, for example. Further descriptionregarding effective release rates of one or more drugs or other agentsfrom a drug supply 322, 324 can be found in commonly-owned DeJuan etal., U.S. application Ser. No. 11/695,545 (filed Apr. 2, 2007 andentitled Nasolacrimal Drainage System Implants for Drug Therapy) whichis herein incorporated by reference in its entirety, including itsdescription of obtaining particular release rates. In some embodiments,the exposed surface of the drug supply 322, 324 can be flush or slightlybelow the proximal end 308 of the first portion 304 or the distal end310 of the second portion 306, respectively, such that the drug supplydoes not protrude outside of the implant body 302. In some embodiments,the exposed surface of the drug supply 322, for instance, can bepositioned above the proximal end 308 such that the drug supply 322 atleast partially protrudes outside of the implant body 302.

The implant body 302 can include an integral feedback or otherprojection 332, such as projections extending laterally at leastpartially from or around a proximal end 308 of the first implant bodyportion 304. In some embodiments, the projection 332 can include a setof wings for use in removing the punctal implant 300 from an implantposition. The removal set of wings can be configured without migrationin mind, as the non-linear configuration of the implant body 302 canprevent migration by assuming a size or shape of the canaliculuscurvature and optionally, the lacrimal canaliculus ampulla. In someembodiments, the projection 332 can be configured to seat against ornear the punctal opening such as for inhibiting or preventing thepunctal implant 300 from passing completely within the lacrimalcanaliculus, or for providing tactile or visual feedback information toan implanting user, e.g., as to whether the implant is fully implanted.The projection 332 can extend laterally in a direction parallel to oraway from an eye when implanted. This will reduce irritation to the eyeas compared to a case in which a portion of the projection extendstoward the eye. In addition, a lateral extension direction of theprojection 332 from the proximal end 308 can be substantially the sameas a lateral extension direction of the second implant body portion 306relative to the distal end 326 of the first implant body portion 304.This can also avoid extension toward the eye. A drug or other agentelution port can extend though a head portion-projection 332, such as toprovide sustained release of the drug supply 322 agent onto an eye.

In various embodiments, the implant body 302 can be molded using anelastic material, such as silicone, polyurethane, NuSil (e.g., NuSil4840 with 2% 6-4800) or an acrylic of a non-biodegradable, partiallybiodegradable or biodegradable nature (i.e., erodeable within the body)allowing a non-linear extending implant body 302 to be formed. In someembodiments, the biodegradable elastic materials can includecross-linked polymers, such as poly(vinyl alcohol). In some embodiments,the implant body 302 can comprise a silicone/polyurethane co-polymer.Other co-polymers that can be used to form the implant body 302 include,but are not limited to, silicone/urethane, silicone/poly(ethyleneglycol) (PEG), and silicone/2hydroxyethyl methacrylate (HEMA). Asdiscussed in commonly-owned Jain et al., Application Ser. No. 61/049,317(filed Apr. 30, 2008 and entitled Drug-Releasing Polyurethane LacrimalInsert), which is herein incorporated by reference in its entirety,urethane-based polymer and copolymer materials allow for a variety ofprocessing methods and bond well to one another.

FIG. 3B illustrates an example embodiment of a cross-sectional view of apunctal implant 300 taken along a line parallel to a longitudinal axisof the implant, such as along line 3B-3B of FIG. 3A. As shown in FIG.3B, the punctal implant 300 can include an implant body 302 includingfirst 304 and second 306 portions. The implant body 302 extends from aproximal end 308 of the first portion 304 to a distal end 310 of thesecond portion 306. In various embodiments, the proximal end 308 candefines a longitudinal proximal axis 312 and the distal end 310 candefine a longitudinal distal axis 314. The implant body 300 can beconfigured such that, when implanted, an at least 45 degree angledintersection 316 exists between the proximal axis 312 and the distalaxis 314 for biasing at least a portion of the implant body 302 againstat least a portion of a lacrimal canaliculus located at or more distalto a canaliculus curvature. In this embodiment, the implant body 300 isconfigured such that the angled intersection 316 is approximately about90 degrees.

In various embodiments, a distal end 326 of the first portion 304 can beintegral with the second portion 306 at or near a proximal end 328 ofthe second end 326. In some embodiments, the second portion 306 caninclude a length having a magnitude less than four times a length of thefirst portion 304. In one embodiment, the second portion 306 can includea length of less than about 10 millimeters, such as is shown in FIG. 3B.In another embodiment, the second portion 306 can include a length lessthan about 2 millimeters.

In certain embodiments, the second portion 306 can comprise an integraldilator 350 to dilate anatomical tissue 352, such one or both of alacrimal punctum or canaliculus to a sufficient diameter as the punctalimplant 300 is being implanted. In this way, the punctal implant 300 canbe implanted in various size ocular anatomies without the need forpre-dilation via a separate enlarging tool. The dilator 350 can beformed so as to not be traumatic to an inner lining of the punctum andthe canaliculus. In some embodiments, a lubricious coating disposed on,or impregnated in, an outer surface of the implant body 302 can be usedto further aid insertion of the punctal implant 300 into the anatomicaltissue 352. In one embodiment, the lubricious coating can include asilicone lubricant.

As shown, the dilator 350 can generally narrow from a location near theproximal end 328 of the second portion 306 to the distal end 310 of thesecond portion 306, such as from a diameter of about 0.6 millimeters toa diameter of about 0.2 millimeters. In some embodiments, an outersurface slope of the dilator 350, as measured from the location near theproximal end 328 of the second portion 306 to the distal end 310 of thesecond portion 306, can be between about 1 degree and about 10 degrees(e.g., 2 degrees, 3 degrees, 4 degrees, or 5 degrees) with respect tothe longitudinal distal axis 314. In some embodiments, the slope of thedilator 350 can be less than 45 degrees with respect to the longitudinaldistal axis 314. Among other factors, a determination of a desirabledilator 350 slope for a given implant situation can be made by balancingan implant body 302 strength desirable for implant with a desire to havea soft, flexible and conforming implant body (e.g., to conform to alacrimal canaliculus anatomy) upon implantation. In some embodiments, adiameter of a dilator tip 354 can be between about 0.2 millimeters andabout 0.5 millimeters.

In certain embodiments, the proximal end 328 of the second implant bodyportion 306 can include a lead extension 356 configured to bias againstat least a portion of a lacrimal canaliculus ampulla when implanted. Inthis embodiment, the lead extension 356 projects proximally from theintersection between the first 304 and second 306 implant body portions,such as in an opposite direction as the extension of the dilator 350.

In certain embodiments, the implant body 302 can include a first cavity318 disposed near the proximal end 308. In this embodiment, the firstcavity 318 extends inward about 2 millimeters or less from the proximalend 308, and houses a first drug-releasing or other agent-releasing drugsupply 322 to provide a sustained drug or other agent release to an eye.In some embodiments, the drug supply 322 can include a plurality oftherapeutic agent inclusions 360, which can be distributed in a matrix362. In some embodiments, the inclusions 360 can comprise a concentratedform of the therapeutic agent (e.g., a crystalline agent form). In someembodiments, the matrix 362 can comprise a silicone matrix or the like,and the distribution of inclusions 360 within the matrix can benon-homogeneous. In some embodiments, the agent inclusions 360 caninclude droplets of oil, such as latanoprost oil. In still otherembodiments, the agent inclusions 360 can comprise solid particles, suchas Bimatoprost particles in crystalline form. The inclusions can be ofmany sizes and shapes. For instance, the inclusions can includemicroparticles having dimensions on the order of about 1 micrometer toabout 100 micrometers.

In the embodiment shown, the drug supply 322 includes a sheath body 366disposed over at least a portion thereof such as to define at least oneexposed surface 368 of the drug supply. The exposed surface 368 can belocated at or near the proximal end 308 of the implant body 302 such asto contact a tear or a tear film fluid and release the therapeutic agentat one or more therapeutic levels over a sustained time period when thepunctal implant 300 is inserted into the lacrimal punctum.

FIG. 4A illustrates an embodiment of a punctal implant 400 that can beinsertable into a lacrimal punctum. In various embodiments, the punctalimplant 400 comprises an implant body 402, including first 404 andsecond 406 portions, which is sized and shaped for at least partialinsertion into a lacrimal punctum. The first portion 404 is formed froma polymer and includes a first diameter 408. The second portion 406 isalso formed from a polymer and includes a base member 412 (e.g., mandrelor spine-like member) having a second diameter 410, which is less thanthe first diameter 408. In an embodiment, the first 404 and second 406portions are integrally coupled and comprise a unitary implant body 402.In an embodiment, the first 404 and second 406 portions are separateelements, which can be coupled to one another via an engagement betweena coupling void and a coupling arm, for instance.

An expandable retention member 414, such as a swellable material, can bebonded or otherwise coupled over the base member 412 such that itenvelops, at least in part, a portion of the base member 412. In anembodiment, the expandable retention member substantially envelops thebase member 412. As the expandable retention member 414 absorbs orotherwise retains lacrimal or other fluid, such as upon insertion into alacrimal punctum, its size increases and its shape may change therebyurging itself against and slightly biasing a wall of the associatedcanaliculus. It is believed that the expandable retention member 414will provide retention comfort to a subject and may improve punctalimplant 400 implant retention via controlled biasing of the canaliculuswall.

The positioning of the expandable retention member 414 over a portion ofthe implant body 402 allows the retention member 414 to be freelyexposed to lacrimal fluid in situ, thereby allowing for a wide range ofpotential expansion rates. Further, the base member 412 provides anadequate coupling surface area to which the expandable retention member414, for example, can adhere such that the material of the expandableretention member 414 does not remain in a lacrimal punctum after thepunctal implant 400 is removed from the subject. As shown in thisembodiment, the expandable retention member 414 can include anon-expanded, “dry or dehydrated” state, which aids insertion through alacrimal punctum and into the associated lacrimal canaliculus. Onceplaced into a lacrimal canaliculus, the expandable retention member 414can absorb or other retain lacrimal fluid to form an expanded structure.

In some embodiments, the implant body 402 can include a cylindrical-likestructure comprising a cavity 416 disposed near a proximal end 418 ofthe first portion 404. In this embodiment, the cavity 416 extends inwardfrom the proximal end 418 and includes a first drug-releasing or otheragent-releasing drug supply 420 to provide a sustained drug or otheragent release to an eye. The drug or other agent release can occur, atleast in part, via an exposed surface of the drug supply 420. In anembodiment, the exposed surface of the drug supply 420 can be positionedabove the proximal end 418 such that the drug supply 420 at leastpartially protrudes outside of the implant body 402. In someembodiments, the exposed surface of the drug supply 420 can be flush orslightly below the proximal end 418 such that the drug supply 420 doesnot protrude outside of the implant body 402.

In some embodiments, by controlling geometry or a drug concentrationgradient near the exposed surface, a predetermined drug or agent releaserate can be achieved. For instance, the exposed surface can beconstructed with a specific geometry or other technique appropriate tocontrol the release rate of the drug or other agent onto an eye, such ason an acute basis, or on a chronic basis between outpatient doctorvisits, for example.

The implant body 402 can include an integral feedback or otherprojection 422, such as projections extending laterally at leastpartially from or around the proximal end 418 of the first implant bodyportion 404. In an embodiment, the projection 422 includes a partiallytrimmed head portion extending 360 degrees around the proximal end 418from an outer implant body surface. In an embodiment, the projection 422includes a full head portion extending 360 degrees around the proximalend 418 from an outer implant body surface. In an embodiment, theprojection 422 includes a cross-sectional shape similar to a flat disk(i.e., relatively flat top and bottom surfaces). In various embodiments,the projection 422 can be configured to seat against or near a punctalopening when the second portion 406 of the implant body 402 ispositioned within the associated canalicular lumen, such as forinhibiting or preventing the punctal implant 400 from passing completelywithin the canalicular lumen, for providing tactile or visual feedbackinformation to an implanting user (e.g., as to whether the implant isfully implanted), or for removing the punctal implant 400 from animplant position. In an embodiment, the projection 422 includes aportion having a diameter of about 0.5-2.0 mm to prevent the punctalimplant 400 from passing down into the canaliculus.

FIG. 4B illustrates an example embodiment of a cross-sectional view of apunctal implant 400 taken along a line parallel to a longitudinal axisof the implant, such as along line 4B-4B of FIG. 4A. As shown in FIG.4B, the punctal implant 400 comprises an implant body 402, includingfirst 404 and second 406 portions, which is sized and shaped for atleast partial insertion into a lacrimal punctum. The first portion 404is formed from a polymer and includes a first diameter 408. The secondportion 406 is also formed from a polymer and includes a base member 412(e.g., mandrel or spine) having a second diameter 410, which is lessthan the first diameter 408. In an embodiment, the base member 412 is atleast about one-third the total length of the implant body 402. In anembodiment, the base member 412 is at least about one-half the totallength of the implant body 402. In the embodiment shown, the implantbody 402 also includes an integral feedback or other projection 422,such as a projection extending laterally at least partially from oraround a proximal end 418 of the first implant body portion 404.

In various embodiments, the implant body 402 can be molded or otherwiseformed using an elastic material, such as silicone, polyurethane orother urethane-based material, or combinations thereof. In anembodiment, one or both of the first 404 and second 406 portions includea urethane-based material. In an embodiment, one or both of the first404 and second 406 portions include a silicone-based material, such as4840® or PurSil®. In an embodiment, one or both of the first 404 andsecond 406 portions include a copolymer material, such aspolyurethane/silicone, urethane/carbonate, silicone/polyethylene glycol(PEG) or silicone/2hydroxyethyl methacrylate (HEMA). In variousembodiments, the implant body 402 is configured to be non-absorbable insitu and is sufficiently strong to address issues of cutting strength(e.g., during insertion and removal of the punctal implant 400) anddimensional stability.

An expandable retention member 414, such as a swellable material, can bebonded or otherwise coupled over the base member 412 such that itenvelops, at least in part, a portion of the base member 412. As theexpandable retention member absorbs or otherwise retains lacrimal fluid,such as upon insertion into a lacrimal punctum, its size increases andits shape may change thereby urging itself against and slightly biasinga wall of the associated canaliculus. In various embodiments, theexpandable retention member 414 can be molded or otherwise formed usinga swellable material. In an embodiment, the expandable retention member414 includes a polyurethane hydrogel, such as TG-2000®, TG-500®, orother urethane-based hydrogel. In an embodiment, the expandableretention member 414 includes a thermoset polymer, which may beconfigured to swell anisotropically. In an embodiment, the expandableretention member 414 includes a gel, which does not maintain its shapeupon expansion, but rather conforms to fit the shape of a canaliculuslumen wall or other surrounding structure.

In some embodiments, the punctal implant 400 includes a base member 412including polyurethane or other urethane-based material and anexpandable retention member 414 including a polyurethane or otherurethane-based swellable material. In an embodiments, a polyurethanehydrogel is coupled directly to an outer surface, such as aplasma-treated outer surface, of the base member 412.

In some embodiments, the punctal implant 400 includes an intermediatemember 450 positioned between a portion of the implant body 402, such asthe base member 412, and a portion of the expandable retention member414. The intermediate member 450 can include a material configured toabsorb, when implanted, a greater amount of lacrimal fluid than thepolymer of the base member 412 but less lacrimal fluid than theswellable polymer of the expandable retention member 414. Theintermediate member 450 can provide the punctal implant 400 withintegrity, such as between a substantially non-swelling polymer of theimplant body 402 and a swelling polymer of the expandable retentionmember 414. For instance, when the polymer of the expandable retentionmember 414 swells upon exposure to moisture, it is possible that theexpanding polymer will, in the absence of the intermediate member 450,swell away from the underlying, non-swelling polymer of the base member412. In an embodiment, the intermediate member 450 includes PurSil® andis dip or otherwise coated onto an outer surface of the base member 412.In an embodiment, the intermediate member 450 includes a polyurethaneconfigured to absorb about 10% to about 500% water, such as Tecophilic®urethanes or Tecophilic® solution grade urethanes. Further discussionregarding the use of an intermediate member 450 positioned between aportion of a first polymer material and a portion of a second polymermaterial, typically different than the first polymer material, can befound in commonly-owned Sim et al., U.S. application Ser. No. 12/432,553(filed Apr. 29, 2009 and entitled Composite Lacrimal Insert and RelatedMethods), which is herein incorporated by reference in its entirety.

In certain embodiments, the implant body 402 can include a cavity 416disposed near the proximal end 418 of the first portion 404. In anembodiment, the first cavity 416 extends inward about 2 millimeters orless from the proximal end 418, and houses a first drug-releasing orother agent-releasing drug supply 420 to provide a sustained drug orother agent release to an eye. In an embodiment, the first cavity 416extends through the implant body 402, and houses a first drug-releasingor other agent-releasing drug supply 420. In various embodiments, thedrug supply 420 stores and slowly dispenses an agent to one or both ofthe eye or the nasolacrimal system as they are leached out, for example,by tear film fluid or other lacrimal fluid. In an embodiment, the drugsupply 420 includes a plurality of therapeutic agent inclusions 452,which can be distributed in a matrix 454. In an embodiment, theinclusions 452 comprise a concentrated form of the therapeutic agent(e.g., a crystalline agent form). In an embodiment, the matrix 454comprises a silicone matrix or the like, and the distribution ofinclusions 452 within the matrix are homogeneous or non-homogeneous. Inan embodiment, the agent inclusions 452 include droplets of oil, such asLatanoprost or other therapeutic agent(s) oil. In still anotherembodiment, the agent inclusions 452 include solid particles, such asBimatoprost particles in crystalline form. The inclusions can be of manysizes and shapes. For instance, the inclusions can includemicroparticles having dimensions on the order of about 1 micrometer toabout 100 micrometers.

In the embodiment shown, the drug supply 420 includes a sheath body 456disposed over at least a portion thereof such as to define at least oneexposed surface 458 of the drug supply. In an embodiment, the sheathbody 456 comprises polyimide. The exposed surface 458 can be located ator near the proximal end 418 of the implant body 402 such as to contacta tear or a tear film fluid and release the therapeutic agent at one ormore therapeutic levels over a sustained time period when the punctalimplant 400 is inserted into a lacrimal punctum.

In certain embodiments, the expandable retention member can include asecond drug-releasing or other agent-releasing drug supply 460 toprovide a sustained drug or other agent release to one or both of a wallof a lacrimal canaliculus or a nasolacrimal system. The drug supply 460can be configured to store and slowly dispense an agent after contactwith lacrimal fluid within a lacrimal canaliculus. In an embodiment, theagent included in the expandable retention member can comprisemedicaments, therapeutic agents, or antimicrobials (e.g., silver).

FIG. 5 illustrates an example embodiment of a cross-sectional view of apunctal implant 500 taken along a line parallel to a longitudinal axisof the implant. As shown in FIG. 5, the punctal implant 500 comprises animplant body 502. In the embodiment shown, the implant body 502 includesan integral feedback or other projection 522, such as a projectionextending laterally at least partially from or around a proximal end 518of the implant body 502. The projection 522 is in the form of a headportion extending radially outwardly from the implant body 502 to adegree sufficient so that at least a portion of the head portion willextend beyond and be exterior to the punctum after insertion of theimplant body 502 distal portions into the canaliculus.

In this embodiment, the implant body 502 is at least partiallyimpregnated with a drug-releasing or other agent-releasing drug supply520. In certain embodiments, the drug supply 520 is disposed within,dispersed throughout, or otherwise contained in the implant body 502.For instance, the implant body 502 can comprise a matrix of a polymericcomponent and one or more agent-releasing drug supplies 520. The one ormore agent-releasing drug supplies 520 can be distributed substantiallythought the matrix and released over time. In this way, the implant body502 can be effective in providing prolonged delivery of one or moretherapeutic agents to an eye, for example, to the outer surface of theeye. As shown in FIG. 5, the implant body 502 can be sized, shaped orotherwise configured to be at least partially retained in a lacrimalcanaliculus while the therapeutic agent is being released. As discussedin commonly-owned Odrich, application Ser. No. 10/825,047 (filed Apr.15, 200 and entitled Drug Delivery via Punctal Plug), which is hereinincorporated by reference in its entirety, the agent of the drug supply520 can be saturated in and released from the implant body 502, such asreleased into tear fluid of the eye or into the nasolacrimal ductsystem.

In various embodiments, an impermeable sheath or coating is disposedover one or more portions of the implant body 502 to control drug supply520 release therefrom. For instance, a non-biodegradable polymer that issubstantially impermeable to the drug supply 520 can be coated around aperiphery of the implant body 502. In some examples, at least onesurface of the implant body 502 is left uncoated or unsheathed to allowthe drug supply 520 stored in the body 502 to release to surroundingbodily tissue or structures. In some examples, the impermeable sheath orcoating includes at least one pore extending from the outer surface ofthe coating to the outer surface of the implant body 502. The at leastone pore can be sized, shaped or otherwise configured to allow drugsupply 520 stored in the body 502 to release to the surrounding bodilytissue or structures, such as unidirectional release to an eye. In someexamples, the at least one pore is etched into the coating, such asusing a laser. In some examples, the at least one pore is formed intothe coating upon the implant dissolving of a salt-impregnated portion ofthe coating. In an example, the impermeable sheath or coating includesparylene.

Making the Implant:

Those of skill in the art will be familiar with various methods usefulfor making the implants described herein. Particular methods aredescribed in the above-identified patent documents, the disclosures ofwhich are incorporated herein by reference in their entirety.

For example, drug cores as described above may be fabricated withdifferent cross sectional sizes of 0.006 inches, 0.012 inches, and 0.025inches. Drug concentrations in the core may be 5%, 10%, 20%, 30% in asilicone matrix. These drug cores can be made with a syringe tube andcartridge assembly, mixing latanoprost or other therapeutic agent(s)with silicone, and injecting the mixture into a polyimide tube which iscut to desired lengths and sealed. The length of the drug cores can beapproximately 0.80 to 0.95 mm, which for a diameter of 0.012 inches(0.32 mm) corresponds to total latanoprost or other therapeutic agent(s)content in the drug cores of approximately 3.5 micrograms, 7 micrograms,14 micrograms and 21 micrograms for concentrations of 5%, 10%, 20% and30%, respectively.

Syringe Tube and Cartridge Assembly: 1. Polyimide tubing of variousdiameters (for example 0.006 inches, 0.0125 inches and 0.025 inches) canbe cut to 15 cm length. 2. The polyimide tubes can be inserted into aSyringe Adapter. 3. The polyimide tube can be adhesive bonded into lueradapter (Loctite, low viscosity UV cure). 4. The end of the assembly canthen be trimmed. 5. The cartridge assembly can be cleaned usingdistilled water and then with methanol and dried in oven at 60.degree.C.

The latanoprost or other therapeutic agent(s) can be mixed withsilicone. Latanoprost or other therapeutic agent(s) may be provided as a1% solution in methylacetate. The appropriate amount of solution can beplaced into a dish and using a nitrogen stream, the solution can beevaporated until only the latanoprost or other therapeutic agent(s)remains. The dish with the latanoprost or other therapeutic agent(s) oilcan be placed under vacuum for 30 minutes. This latanoprost or othertherapeutic agent(s) can then be combined with silicone, with threedifferent concentrations of latanoprost or other therapeutic agent(s)(5%, 10% and 20%) in silicone NuSil 6385 being injected into tubing ofdifferent diameters (0.006 in, 0.012 in and 0.025 inches) to generate3×3 matrixes. The percent of latanoprost or other therapeutic agent(s)to silicone is determined by the total weight of the drug matrix.Calculation: Weight of latanoprost or other therapeutic agent(s)/(weightof latanoprost or other therapeutic agent(s)+weight ofsilicone)×100=percent drug.

The tube can then be injected: 1. The cartridge and polyimide tubesassembly can be inserted into a 1 ml syringe. 2. One drop of catalyst(MED-6385 Curing Agent) can be added in the syringe. 3. Excess catalystcan be forced out of the polyimide tube with clean air. 4. The syringecan then be filled with silicone drug matrix. 5. The tube can then beinjected with drug matrix until the tube is filled or the syringeplunger becomes too difficult to push. 6. The distal end of thepolyimide tube can be closed off and pressure can be maintained untilthe silicone begins to solidify. 7. Allow to cure at room temperaturefor 12 hours. 8. Place under vacuum for 30 minutes. 9. The tube can thenbe place in the correct size trim fixture (prepared in house to holddifferent size tubing) and drug inserts can be cut to length (0.80-0.95mm).

Release of Latanoprost or Other Therapeutic Agent(s) at EffectiveLevels:

The rate of release of latanoprost or other therapeutic agent(s) can berelated to the concentration of latanoprost or other therapeuticagent(s) dissolved in the drug core. In some embodiments, the drug corecomprises non-therapeutic agents that are selected to provide a desiredsolubility of the latanoprost or other therapeutic agent(s) in the drugcore. The non-therapeutic agent of the drug core can comprise polymersas described herein, and additives. A polymer of the core can beselected to provide the desired solubility of the latanoprost or othertherapeutic agent(s) in the matrix. For example, the core can comprisehydrogel that may promote solubility of hydrophilic treatment agent. Insome embodiments, functional groups can be added to the polymer toprovide the desired solubility of the latanoprost or other therapeuticagent(s) in the matrix. For example, functional groups can be attachedto silicone polymer.

Additives may be used to control the concentration of latanoprost orother therapeutic agent(s) by increasing or decreasing solubility of thelatanoprost or other therapeutic agent(s) in the drug core so as tocontrol the release kinetics of the latanoprost or other therapeuticagent(s). The solubility may be controlled by providing appropriatemolecules or substances that increase or decrease the content oflatanoprost or other therapeutic agent(s) in the matrix. The latanoprostor other therapeutic agent(s) content may be related to the hydrophobicor hydrophilic properties of the matrix and latanoprost or othertherapeutic agent(s). For example, surfactants and salts can be added tothe matrix and may increase the content of hydrophobic latanoprost inthe matrix. In addition, oils and hydrophobic molecules can be added tothe matrix and may increase the solubility of hydrophobic treatmentagent in the matrix.

Instead of or in addition to controlling the rate of migration based onthe concentration of latanoprost or other therapeutic agent(s) dissolvedin the matrix, the surface area of the drug core can also be controlledto attain the desired rate of drug migration from the core to the targetsite. For example, a larger exposed surface area of the core willincrease the rate of migration of the treatment agent from the drug coreto the target site, and a smaller exposed surface area of the drug corewill decrease the rate of migration of the latanoprost or othertherapeutic agent(s) from the drug core to the target site. The exposedsurface area of the drug core can be increased in any number of ways,for example by any of castellation of the exposed surface, a poroussurface having exposed channels connected with the tear or tear film,indentation of the exposed surface, protrusion of the exposed surface.The exposed surface can be made porous by the addition of salts thatdissolve and leave a porous cavity once the salt dissolves. Hydrogelsmay also be used, and can swell in size to provide a larger exposedsurface area. Such hydrogels can also be made porous to further increasethe rate of migration of the latanoprost or other therapeutic agent(s).

Further, an implant may be used that includes the ability to release twoor more drugs in combination, such as the structure disclosed in U.S.Pat. No. 4,281,654 (Shell). For example, in the case of glaucomatreatment, it may be desirable to treat a patient with multipleprostaglandins or a prostaglandin and a cholinergic agent or anadrenergic antagonist (beta blocker), such as Alphagan™, or latanoprostand a carbonic anhydrase inhibitor.

In addition, drug impregnated meshes may be used such as those disclosedin US Patent Publication No. 2002/0055701 (serial no. 77/2693) orlayering of biostable polymers as described in US Patent Publication No.2005/0129731 (serial no. 97/9977), the disclosures of which areincorporated herein in their entirety. Certain polymer processes may beused to incorporate latanoprost or other therapeutic agent(s) into thedevices of the present invention; such as so-called “self-deliveringdrugs” or PolymerDrugs (Polymerix Corporation, Piscataway, N.J.) aredesigned to degrade only into therapeutically useful compounds andphysiologically inert linker molecules, further detailed in US PatentPublication No. 2005/0048121 (serial no. 86/1881; East), herebyincorporated by reference in its entirety. Such delivery polymers may beemployed in the devices of the present invention to provide a releaserate that is equal to the rate of polymer erosion and degradation and isconstant throughout the course of therapy. Such delivery polymers may beused as device coatings or in the form of microspheres for a drug depotinjectable (such as a reservoir of the present invention). A furtherpolymer delivery technology may also be configured to the devices of thepresent invention such as that described in US Patent Publication No.2004/0170685 (serial no. 78/8747; Carpenter), and technologies availablefrom Medivas (San Diego, Calif.).

In specific embodiments, the drug core matrix comprises a solidmaterial, for example silicone, that encapsulates inclusions of thelatanoprost or other therapeutic agent(s). The drug comprises moleculeswhich are very insoluble in water and slightly soluble in theencapsulating drug core matrix. The inclusions encapsulated by the drugcore can be micro-particles having dimensions from about 1 micrometer toabout 100 micrometers across. The drug inclusions can comprise dropletsof oil, for example latanoprost oil. The drug inclusions can dissolveinto the solid drug core matrix and substantially saturate the drug corematrix with the drug, for example dissolution of latanoprost oil intothe solid drug core matrix. The drug dissolved in the drug core matrixis transported, often by diffusion, from the exposed surface of the drugcore into the tear film. As the drug core is substantially saturatedwith the drug, in many embodiments the rate limiting step of drugdelivery is transport of the drug from the surface of the drug corematrix exposed to the tear film. As the drug core matrix issubstantially saturated with the drug, gradients in drug concentrationwithin the matrix are minimal and do not contribute significantly to therate of drug delivery. As surface area of the drug core exposed to thetear film is nearly constant, the rate of drug transport from the drugcore into the tear film can be substantially constant. Naturallyoccurring surfactants may affect the solubility of the latanoprost orother therapeutic agent(s) in water and molecular weight of the drug canaffect transport of the drug from the solid matrix to the tear. In manyembodiments, the latanoprost or other therapeutic agent(s) is nearlyinsoluble in water and has a solubility in water of about 0.03% to0.002% by weight and a molecular weight from about 400 grams/mol. toabout 1200 grams/mol.

In many embodiments the latanoprost or other therapeutic agent(s) has avery low solubility in water, for example from about 0.03% by weight toabout 0.002% by weight, a molecular weight from about 400 grams per mole(g/mol) to about 1200 g/mol, and is readily soluble in an organicsolvent. Latanoprost is a liquid oil at room temperature, and has anaqueous solubility of 50 micrograms/mL in water at 25 degrees C., orabout 0.005% by weight and a M.W. of 432.6 g/mol.

Naturally occurring surfactants in the tear film, for example surfactantD and phospholipids, may effect transport of the drug dissolved in thesolid matrix from the core to the tear film. In some embodiments thedrug core can be configured in response to the surfactant in the tearfilm to provide sustained delivery of latanoprost or other therapeuticagent(s) into the tear film at therapeutic levels. For example,empirical data can be generated from a patient population, for example10 patients whose tears are collected and analyzed for surfactantcontent. Elution profiles in the collected tears for a drug that issparingly soluble in water can also be measured and compared withelution profiles in buffer and surfactant such that an in vitro model oftear surfactant is developed. An in vitro solution with surfactant basedon this empirical data can be used to adjust the drug core in responseto the surfactant of the tear film.

The drug cores may also be modified to utilize carrier vehicles such asnanoparticles or microparticles depending on the size of the molecule tobe delivered such as latent-reactive nanofiber compositions forcomposites and nanotextured surfaces (Innovative Surface Technologies,LLC, St. Paul, Minn.), nanostructured porous silicon, known asBioSilicon™, including micron sized particles, membranes, woven fiversor micromachined implant devices (pSividia, Limited, UK) and proteinnanocage systems that target selective cells to deliver a drug(Chimeracore).

In many embodiments, the drug insert comprises of a thin-walledpolyimide tube sheath with a drug core comprising latanoprost dispersedin Nusil 6385 (MAF 970), a medical grade solid silicone that serves asthe matrix for drug delivery. The distal end of the drug insert issealed with a cured film of solid Loctite 4305 medical grade adhesive.The drug insert may be placed within the bore of the punctal implant,the Loctite 4305 adhesive does not come into contact with either tissueor the tear film. The inner diameter of the drug insert can be 0.32 mm;and the length can be 0.95 mm. At least four latanoprost concentrationsin the finished drug product can be employed: Drug cores can comprise3.5, 7, 14 or 21 micrograms latanoprost, with percent by weightconcentrations of 5, 10, 20, or 30% respectively. Assuming an overallelution rate of approximately 100 ng/day, the drug core comprising 14micrograms of latanoprost is configured to deliver drug forapproximately at least 100 days, for example 120 days. The overallweight of the drug core, including latanoprost or other therapeuticagent(s), can be about 70 micrograms. The weight of the drug insertincluding the polyimide sleeve can be approximately 100 micrograms.

In many embodiments, the drug core may elute with an initial elevatedlevel of latanoprost or other therapeutic agent(s) followed bysubstantially constant elution of the latanoprost or other therapeuticagent(s). In many instances, an amount of latanoprost or othertherapeutic agent(s) released daily from the core may be below thetherapeutic levels and still provide a benefit to the patient. Anelevated level of eluted latanoprost or other therapeutic agent(s) canresult in a residual amount of latanoprost or other therapeutic agent(s)or residual effect of the latanoprost or other therapeutic agent(s) thatis combined with a sub-therapeutic amount of latanoprost or othertherapeutic agent(s) to provide relief to the patient. In embodimentswhere therapeutic level is about 80 ng per day, the device may deliverabout 100 ng per day for an initial delivery period. The extra 20 ngdelivered per day can have a beneficial effect when latanoprost or othertherapeutic agent(s) is released at levels below the therapeutic level,for example at 60 ng per day. As the amount of drug delivered can beprecisely controlled, an initial elevated dose may not result incomplications or adverse events to the patient.

In certain embodiments, the methods of the invention result in apercentage reduction in intraocular pressure of approximately 28%. Insome embodiments, the methods of the invention results in a percentagereduction or decrease in intraocular pressure of approximately 30%,approximately 29%, approximately 28%, approximately 27%, approximately26%, approximately 25%, approximately 24%, approximately 23%,approximately 22%, approximately 21%, or approximately 20%. In certainembodiments, the methods of the invention result in a percentagereduction or decrease in intraocular pressure of at least 30%, at least29%, at least 28%, at least 27%, at least 26%, at least 25%, at least24%, at least 23%, at least 22%, at least 21%, at least 20%, at least15%, or at least 10%.

In certain embodiments, the methods of the invention result in areduction in intraocular pressure from baseline over a treatment periodof about 6 mm Hg, about 5 mm Hg, about 4 mm Hg, about 3 mm Hg or about 2mm Hg. In certain embodiments, the methods of the invention result in areduction in intraocular pressure from baseline of at least 2 mm Hg, atleast 3 mm Hg, at least 4 mm Hg, at least 5 mm Hg, at least 6 mm Hg, orat least 7 mm Hg. In some embodiments, intraocular pressure is reducedto less than or equal to 21 mm Hg, less than or equal to 20 mm Hg, lessthan or equal to 19 mm Hg, less than or equal to 18 mm Hg, less than orequal to 17 mm Hg, less than or equal to 16 mm Hg, less than or equal to15 mm Hg, less than or equal to 14 mm Hg, less than or equal to 13 mmHg, or less than or equal to 12 mm Hg.

In an embodiment, the implants and methods of the invention provide a90-day course of treatment. In other embodiments, the implants andmethods of the invention provide a 60-day course of treatment. In stillother embodiments, the implants and methods of the invention provide a45-day course of treatment. In still other embodiments, the implants andmethods of the invention provide a 30-day course of treatment, dependingupon the disease to be treated and the therapeutic agent to bedelivered. Other embodiments include one week, two weeks, three weeks,four weeks, five weeks, six weeks, seven weeks, eight weeks, nine weeks,ten weeks, eleven weeks, or twelves weeks of treatment. In someembodiments, effective levels of latanoprost or other therapeuticagent(s) release during the entire course of treatment. In a furtherembodiment, the variability in intraocular pressure over the course oftreatment is less than about 1 mm Hg. In other embodiments, thevariability in intraocular pressure over the course of treatment is lessthan about 2 mm Hg. In other embodiments, the variability in intraocularpressure over the course of treatment is less than about 3 mm Hg.

The implants described herein may be inserted into the superior punctum,the inferior punctum, or both, and may be inserted into one or both eyesof the subject.

As described below, a study was conducted using five test subjects ≧18years of age who had a diagnosis of ocular hypertension or glaucoma atbaseline. Sustained release implants comprising 14 microgramslatanoprost were inserted into the puncta of the subjects. Within sevendays, a mean reduction in intraocular pressure of 6 mm Hg was observed.This reduction was maintained over approximately three months.

The invention can be described by the following non-limiting examples.

Example 1

An open-label, prospective study was conducted with patients beingfollowed for up to 3 months post-placement. Patients were males orfemales 18 years of age or older, with a diagnosis of ocularhypertension or glaucoma, who had two sequential measurements (at least48 hours apart) of intraocular pressure of 22 mmHg or greater after anappropriate drug washout period (see Table 2 below).

Implant:

The Punctal Plug Drug Delivery System (PPDS) consisted of a drug insertconfigured to be placed in a suitable commercially available punctalimplant with a pre-existing bore. All materials used in the constructionof the drug insert were medical grade materials that passed a battery ofsafety/toxicity tests. The drug insert was a thin-walled polyimide tubethat was filled with latanoprost dispersed in Nusil 6385, a curedmedical grade solid silicone. The cured silicone served as the solid,non-erodible matrix from which latanoprost slowly eluted. The druginsert was sealed at the distal end with a cured film of solid Loctite4305 medical grade adhesive (cyanoacrylate). The polyimide sleeve wasinert and, together with the adhesive, provided structural support and abarrier to both lateral drug diffusion and drug diffusion through thedistal end of the drug insert. The drug insert was seated in the bore ofthe punctal implant and was held in place via an interference fit. Theassembled system was packaged and sterilized.

Procedures:

Patients were fitted with a punctal implant after the first visit whereocular hypertension was demonstrated. Patients were evaluated at thefollowing qualification visit to determine if the punctal implant wasstill in place. Following a subsequent baseline visit, subjects receivedone Punctal Plug Drug Delivery System in the inferior punctum of botheyes. If at any exam a punctal implant was not in place, a new PunctalPlug Drug Delivery System was inserted. The delivery system was placedin the inferior or superior punctum after the appropriate washoutperiod, as defined in Table 2 below. If during subsequent visits thePunctal Plug System was not present a replacement device was inserted.

Placement and removal of the Punctum Plug Drug Delivery System wasaccomplished in the same manner as for other commercially availablepunctal implants. Generally, for placement the size of a punctal implantto be used was determined by using suitable magnification or, ifprovided, using a sizing tool that accompanied the punctal implant. Thepatient's punctum was dilated if necessary to fit the punctal implant. Adrop of lubricant was applied if necessary to facilitate placement ofthe implant into the punctum. Using an appropriate placement instrumentthe implant was inserted into the superior or inferior punctum of theeye. After placement, the cap of the implant was visible. This processwas repeated for the patient's other eye. For removal of the implant,small surgical forceps were used to securely grasp the implant at thetube section below the cap. Using a gentle tugging motion the implantwas gently retrieved.

TABLE 2 Recommended Washout Period Drug Class Sample Agent(s) WashoutPeriod Prostaglandin analogs Latanoprost (Xalatan), 4 weeks Bimatoprost(Lumigan), Travoprost (Travatan) Beta blocker Betaxolol (Betoptic) 3weeks Timolol (Betimol) Adrenergic agonists Apraclonidine (lopidine) 2weeks Dipivefrin (Propine) AH other IOP lowering Brinzolamide (Azopt) 72hours medications Dorzolamide (Trusopt) Pilocarpine (Pilocar)

During the course of the study, intraocular pressure was measured byGoldmann applanation tonometry. Both a topical anesthetic andfluorescein were applied. This was accomplished by use of a combinationproduct (e.g., Fluress®, benoxinate and fluorescein), or by separateapplication of a local anesthetic and fluorescein for cornealassessments. Immediately thereafter, intraocular pressure was measuredusing an applanation method. Efficacy was evaluated as change in IOPfrom the baseline.

Drug Release Kinetics In Vitro:

Multiple in vitro experiments have been performed with several medicalgrade silicone formulations to demonstrate the ability to controllatanoprost elution rates. The amount of latanoprost in the commerciallyavailable product Xalatan® is approximately 1.5 micrograms/drop. Apunctal implant delivery system that elutes approximately 100 ng/day oflatanoprost therefore delivers only about 6% of the amount of drug as inXalatan®. For this reason the punctal implant device should not pose anydrug safety risk to the patient.

Adverse Events:

The risks associated with the device are possible ocular irritation dueto the punctal implant or ineffective relief of ocular hypertension. Thetotal drug content for the punctal implant system is equivalent to 10-20drops of Xalatan®. Safety was evaluated by assessment of the ocularsigns at slit lamp examination, intraocular pressure (IOP), visualacuity, and by determining the incidence and severity of adverse events.

Results:

The IOP for each subject is the average IOP of 2 eyes, unless only 1 eyeis treated. Thus, N=10 eyes equated to 5 subjects. N=10 eyes on Days0-28, N=9 eyes on Day 52, N=6 eyes on Day 88-105 (2 subjects excluded atDay 88 and beyond for starting Xalatan® in fellow eye, which had lostthe implant; thus 3 subjects remained in the study from day 88-105). AtDay 105, 1 subject out of the 3 subjects lost efficacy (IOP is within 2mmHg below baseline).

As shown in FIG. 1 and Table 3, post wash-out mean baseline IOP was22.9±0.9 mmHg. Seven days after PPDS placement, mean IOP decreased to16.1±1.1 mmHg and remained stable throughout the follow-up period. AtDay 88, mean IOP was 16.5±1.2 mmHg representing a 28% pressure decreasefrom baseline (p<0.05). These results demonstrate that treatment withthe sustained release punctal implant delivery system is safe andeffective in the studied subject population.

TABLE 3 Mean intraocular pressure in subjects treated with 14 μgLatanoprost Punctal Plug Delivery System Standard Study Day N Mean IOPDeviation 0 5 subjects (10 eyes) 22.9 0.9 1 5 subjects (10 eyes) 19.71.2 7 5 subjects (10 eyes) 16.1 1.1 14 5 subjects (10 eyes) 15.8 1.2 215 subjects (10 eyes) 15.8 1.6 28 5 subjects (10 eyes) 16.2 1.4 52 5subjects (9 eyes)  15.9 0.7 88 3 subjects (6 eyes)  16.8 1.4 105 3subjects (6 eyes)  19.0 3.0

Example 2

A randomized, masked, phase 2 study (“CORE study”) was conducted toassess the IOP lowering effect of a Latanoprost Punctal Plug DeliverySystem (L-PPDS) with a sustained-release drug-eluting core. Sixty-oneopen-angle glaucoma or ocular hypertension patients with post wash-outIOP between 21 and 30 mmHg were randomized equally to one of threetreatment groups, L-PPDS containing a dose of 3.5, 14, or 21 μg oflatanoprost, and followed for up to 12 weeks. Main outcome measures wereIOP change from baseline and safety.

Efficacy Results:

The analysis of preliminary efficacy was based on the proportion ofsubjects in each treatment group who did not lose efficacy, IOP, and theIOP changes and percentage changes from baseline at each visit. Theintent-to-treat (ITT) data set includes data from all randomizedsubjects. No subjects were excluded because of protocol violations. TheITT data set was used for analyzing all study variables.

Study findings show that there was an IOP lowering effect among allthree doses, with a mean decrease from baseline of 20% at week 12. MeanIOP at screening was 16.8 mmHg; after washout, mean IOP was 24.4±2.1mmHg. FIGS. 9 and 10 show mean IOP change from baseline for 3.5, 14, and21 microgram implants at 4, 8 and 12 weeks. At week 8, patients had amean reduction in IOP of −3.6±2.4, 4.2±3.7, and 4.4±2.4 mmHg in the 3.5,14, and 21 μg groups respectively (n=17, 15, and 15). At week 12, meanreduction in IOP was −5.4±2.7; −4.8±3.2; and −4.9±2.1 respectively(n=13, 12, and 13), representing a 20% drop from baseline at Week 12.The retention rate of the L-PPDS was 75%.

FIG. 11 shows decrease in IOP from baseline at week 12 for each of thetreatment groups. Certain reductions in IOP are shown on the X axis. Thepercentage of patients in each treatment group exhibiting thosereductions are shown on the Y axis.

FIGS. 12-15 compare the efficacy of the L-PPDS to other topical glaucomamedication.

Safety Results:

The L-PPDS was well-tolerated over the testing period (see FIG. 16). Theoverall adverse events ranged from 1.6% to 14.8% and were not dosedependent. The most common adverse events were increased lacrimation(tear production) and ocular discomfort (14.8% and 9.8%, respectively)which were mild and transient in nature and were most likely resolvedduring the adaptation period to punctal implant wear. Ocular hyperemiaand punctate keratitis rates were 1.6% each. At Week 12, 89% of patientsrated L-PPDS comfort as ‘no awareness’ and 8% ‘mild awareness,’ whiletearing was rated ‘none’ (78%), ‘occasional’ (14%), or ‘mild’ (5%). Theremaining 3% of patients did not have a comfort and tearing assessmentat Week 12. Nineteen patients discontinued before the Week 12 visit dueto loss of efficacy/inadequate IOP control.

FIG. 16 shows adverse events associated with the L-PPDS for eachtreatment group and all treatment groups combined. Reported adverseevents included conjunctival hyperemia, eye pruritus, eyelid margincrusting, foreign body sensation, increase in lacrimation, oculardiscomfort, ocular hyperemia and punctate keratitis.

FIGS. 17 and 18 compare adverse events of the L-PPDS to adverse eventspreviously reported for eye drop formulations of other medicationsincluding travoprost, timolol, latanoprost, and bimatoprost. Thefollowing were used for comparison with L-PPDS and are incorporated byreference herein in their entirety: Travoprost Compared With Latanoprostand Timolol in Patients With Open-angle Glaucoma or Ocular Hypertension.Am J Ophthalmol 2001; 132:472-484 (additional reported AEs includedocular pain, cataract, dry eye, blepharitis, blurred vision); ASix-month Randomized Clinical Trial Comparing the IntraocularPressure-lowering efficacy of Bimatoprost and Latanoprost in PatientsWith Ocular Hypertension or Glaucoma. Am J Ophthalmol 2003; 135:55-63(additional reported AEs included eyelash growth); One-Year, RandomizedStudy Comparing Bimatoprost and Timolol in Glaucoma and OcularHypertension. Arch Ophthalmol V 120 October 2002 1286-1293 (additionalreported AEs included eyelash growth, eye dryness, eye pain; abimatoprost BID group was also included and showed a higher incidence ofadverse events); and Xalatan Ophthalmic Solution 0.005% (50 mg/mL)(Pharmacia) Jun. 5, 1996 Approval: Medical Officers Review, pp. 93,98-100. Provided by FOI Services.

Summary:

CORE is the first known randomized, parallel group, multicenter US trialinvestigating a sustained and controlled punctal implant drug deliverysystem for glaucoma. A mean IOP decrease of 20% was seen at 3 months.The ocular implants were well tolerated; no notable safety issues wereobserved.

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The above Detailed Description includes references to the accompanyingdrawings, which form a part of the Detailed Description. The drawingsshow, by way of illustration, specific embodiments in which theinvention can be practiced. These embodiments are also referred toherein as “examples.” All publications, patents, and patent documentsreferred to in this document are incorporated by reference herein intheir entirety, as though individually incorporated by reference. In theevent of inconsistent usages between this document and those documentsso incorporated by reference, the usage in the incorporated reference(s)should be considered supplementary to that of this document; forirreconcilable Inconsistencies, the usage in this document controls.

The above description is intended to be illustrative, and notrestrictive. For example, the above-described examples (or one or morefeatures thereof) can be used in combination with each other. Otherembodiments can be used, such as by one of ordinary skill in the artupon reviewing the above description. Also, in the above DetailedDescription, various features can be grouped together to streamline thedisclosure. This should not be interpreted as intending that anunclaimed disclosed feature is essential to any claim. Rather, inventivesubject matter can lie in less than all features of a particulardisclosed embodiment. Thus, the following claims are hereby incorporatedinto the Detailed Description, with each claim standing on its own as aseparate embodiment. The scope of the invention should be determinedwith reference to the appended claims, along with the full scope ofequivalents to which such claims are entitled.

Concentrations, amounts, percentages, time periods, etc., of variouscomponents or use or effects of various components of this invention,including but not limited to the drug core, indications of reduction inIOP, and treatment time periods, are often presented in a range orbaseline threshold format throughout this patent document. Thedescription in range or baseline threshold format is merely forconvenience and brevity and should not be construed as an inflexiblelimitation on the scope of the invention. Accordingly, the descriptionof a range or baseline threshold should be considered to havespecifically disclosed all the possible subranges as well as individualnumerical values within that range or above that baseline threshold. Forexample, description of a drug core having a drug or other agentconcentration range of 3.5 micrograms to 135 micrograms should beconsidered to have specifically disclosed subranges, such as 5micrograms to 134 micrograms, 6 micrograms to 135 micrograms, 40micrograms to 100 micrograms, 44 micrograms to 46 micrograms, etc., aswell as individuals numbers within that range, such as 41 micrograms, 42micrograms, 43 micrograms, 44 micrograms, 45 micrograms, 46 micrograms,47 micrograms, 48 micrograms, etc. This construction applies regardlessof the breadth of the range or baseline threshold and in all contextsthroughout this disclosure.

1-27. (canceled)
 28. A method for reducing intraocular pressure in aneye of a patient having an elevated baseline intraocular pressure of 21to 30 mmHg, comprising: administering to the patient a latanoprostsustained release topical formulation for at least four weeks whereinthe intraocular pressure is reduced by at least about 10% from baselineat week 4, wherein the latanoprost sustained release topical formulationcontinually releases latanoprost from a punctal implant to the eye ofthe patient, and wherein the punctal implant comprises a first axis,defined by a proximal end of the implant, and a second axis, defined bythe distal end of the implant, and at least an angled intersectionbetween the first and second axis from about 45 degrees to about 135degrees.
 29. The method of claim 28, wherein the punctal implant isconfigured to inhibit expulsion when implanted in a punctum of the eye.30. The method of claim 28, wherein the intraocular pressure is reducedan amount selected from the group consisting of at least 15% frombaseline, at least 20% from baseline, and at least 25% from baseline.31. The method of claim 28, wherein the latanoprost is released for atleast 8 weeks.
 32. The method of claim 28, wherein the latanoprost isreleased for at least 12 weeks.
 33. The method of claim 28, wherein thelatanoprost sustained release topical formulation is contained within adrug insert disposed in the punctal implant, wherein the drug insertcomprises a matrix and an impermeable sheath body.
 34. The method ofclaim 33, wherein the matrix comprises silicone.
 35. The method of claim33, wherein the impermeable sheath body comprises polyimide.
 36. Themethod of claim 28, wherein the reduction in intraocular pressure ismaintained for a continuous period of time selected from the groupconsisting of: up to about 28 days, up to about 56 days, up to about 84days, and up to about 105 days.
 37. The method of claim 28, wherein thereduction in intraocular pressure is maintained for a continuous periodof time selected from the group consisting of: up to about 4 weeks, upto about 8 weeks, and up to about 12 weeks.
 38. The method of claim 28,wherein the latanoprost sustained release formulation releases less thana therapeutic dose of latanoprost as compared to Xalatan on a dailybasis.
 39. The method of claim 28, wherein latanoprost sustained releaseformulation releases less than an average 1.5 micrograms of latanoproston a daily basis.
 40. The method of claim 28, wherein the latanoprostsustained release formulation comprises at least about 3.5 micrograms oflatanoprost.
 41. The method of claim 28, wherein the punctal implant isinserted into an upper punctum of the eye.
 42. The method of claim 28,wherein the punctal implant is inserted into a lower punctum of the eye.43. The method of claim 28, wherein the punctal implant is inserted intoan upper or lower punctum of one eye of the patient.
 44. The method ofclaim 28, wherein the punctal implant is inserted into an upper or lowerpunctum of both eyes of the patient.
 45. A method for reducingintraocular pressure in an eye of a patient having an elevated baselineintraocular pressure of 21 to 30 mmHg, comprising: administering to thepatient a latanoprost sustained release topical formulation for at leastfour weeks wherein the intraocular pressure is reduced by at least 10%from baseline at week 4, wherein the latanoprost sustained releasetopical formulation continually releases latanoprost from a punctalimplant to the eye of the patient at an average daily rate less than atherapeutic dose of latanoprost as compared to Xalatan, and wherein thepunctal implant comprises a first axis, defined by a proximal end of theimplant, and a second axis, defined by the distal end of the implant,and at least an angled intersection between the first and second axisfrom about 45 degrees to about 135 degrees.
 46. The method of claim 45,wherein the intraocular pressure is reduced an amount selected from thegroup consisting of at least 15% from baseline, at least 20% frombaseline, and at least 25% from baseline.
 47. The method of claim 45,wherein the latanoprost is released for at least 8 weeks.
 48. The methodof claim 45, wherein the latanoprost is released for at least 12 weeks.49. The method of claim 45, wherein the latanoprost sustained releasetopical formulation is contained within a drug insert disposed in thepunctal implant, wherein the drug insert comprises a matrix and animpermeable sheath body.
 50. The method of claim 49, wherein the matrixcomprises silicone.
 51. The method of claim 49, wherein the impermeablesheath body comprises polyimide.
 52. The method of claim 45, whereinlatanoprost sustained release formulation releases less than an average1.5 micrograms of latanoprost on a daily basis.
 53. The method of claim45, wherein the punctal implant is inserted into an upper punctum of theeye.
 54. The method of claim 45, wherein the punctal implant is insertedinto a lower punctum of the eye.
 55. A method for reducing intraocularpressure in an eye of a patient having an elevated baseline intraocularpressure of 21 to 30 mmHg, comprising: administering to the patient alatanoprost sustained release topical formulation for at least fourweeks wherein the intraocular pressure is reduced by at least 10% frombaseline at week 4, wherein the latanoprost sustained release topicalformulation continually releases latanoprost from a punctal implant tothe eye of the patient at an average daily rate less than about 1.5micrograms of latanoprost, and wherein the punctal implant comprises afirst axis, defined by a proximal end of the implant, and a second axis,defined by the distal end of the implant, and at least an angledintersection between the first and second axis from about 45 degrees toabout 135 degrees.